KR20130098154A - Novel compounds for the treatment of diseases associated with amyloid or amyloid-like proteins - Google Patents

Abstract

The present invention relates to novel compounds that can be used in the treatment of disorders and disorders associated with amyloid proteins, such as Alzheimer's disease, and groups of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used for the treatment of eye diseases associated with pathological abnormalities / changes of tissues of the visual system. The invention also relates to the use of these compounds and to pharmaceutical compositions comprising these compounds for the manufacture of medicaments for the treatment or prevention of diseases or conditions associated with amyloid and / or amyloid-like proteins. Also described are methods of treating or preventing diseases or conditions associated with amyloid and / or amyloid-like proteins.

Description

NOVEL COMPOUNDS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH AMYLOID OR AMYLOID OR AMYLOID-LIKE PROTEINS}

The present invention relates to novel compounds that can be used in the treatment of disorders and abnormalities associated with amyloid proteins such as Alzheimer's Disease, and groups of diseases or conditions associated with amyloid-like proteins. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the manufacture of medicaments for the treatment of diseases or conditions associated with amyloid or amyloid-like proteins. Methods of treating diseases or conditions associated with amyloid or amyloid-like proteins are also described.

Compounds of the invention are also associated with pathological abnormalities / changes in the tissues of the visual system, in particular ocular diseases associated with amyloid-beta-related pathological abnormalities / changes in the tissues of the visual system, such as neuronal degradation. It can be used for the treatment of. Such pathological abnormalities include, for example, visual cortex resulting in cortical visual deficit; Optic nerve and anterior chamber that bring glaucoma; A lens that causes cataracts due to beta-amyloid deposition; A vitreous body that causes amyloidosis; Primary retinal degeneration and macular degeneration, such as retinas resulting in age-related macular degeneration; Optic nerve drusen, optic neuropathy that causes optic neuropathy and optic neuritis; And lattice dystrophy in the cornea of the eye.

Many aging diseases are based on or associated with amyloid or amyloid-like proteins and are characterized in part by the formation of extracellular deposits of amyloid or amyloid-like substances that contribute to the pathogenesis mechanism of the disease as well as progression. These diseases include, but are not limited to, neurological disorders such as Alzheimer's disease (AD), diseases or conditions characterized by loss of cognitive memory, such as, for example, mild cognitive impairment (MCI), Lewy body dementia. dementia, Down's syndrome, amyloid hereditary cerebral hemorrhage with amyloidosis (Dutch type); Guam Parkinson-Dementia complex. Other diseases based on or associated with amyloid-like proteins include progressive supranuclear palsy, multiple sclerosis; Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, amyotropic lateral sclerosis (ALS), inclusion-body myositis (IBM), adult-onset diabetes (Adult) Onset Diabetes); Senile cardiac amyloidosis; Endocrine tumors, and different tissues of the eye, such as cortical visual defects; Optic nerve and anterior chambers, including glaucoma; Lenses including cataracts due to beta-amyloid deposition; Vitreous including ocular amyloidosis; Primary retinal degeneration and macular degeneration, especially retinas including age-related macular degeneration; Optic nerves including optic nerve drusen, optic neuropathy and optic neuritis; And other diseases, including amyloid-related eye diseases targeting the cornea, including lattice dystrophy.

Although the pathogenic mechanisms of these diseases may vary, their characteristic deposits often contain many common molecular components. To a significant extent, this can contribute to the local activation of the pro-inflammatory pathway, leading to the activation of the activated complement component, acute phase reactant, immune modulator, Concurrent deposition of an inflammatory mediator (concurrent deposition).

Alzheimer's disease (AD) is a neurological disorder that is thought to be primarily due to amyloid plaques, which are accumulations of abnormal deposits of proteins in the brain. The most common type of amyloid found in the brains of diseased individuals consists mainly of Aβ fibrils. Scientific evidence demonstrates that increased production and accumulation of beta-amyloid proteins in plaques leads to neuronal cell death, which contributes to the development and progression of AD. Subsequently, the loss of neurons in the strategic brain region causes a decrease in neurotransmitters and damage to memory. Proteins primarily essential for plaque formation include amyloid precursor protein (APP) and two presenilins (presenilin I and presenilin II). Sequential cleavage of amyloid precursor protein (APP), which is constitutively expressed and catabolized by enzyme β and γ secretase, releases 39 to 43 amino acid Aβ peptides. Degradation of APP likewise increases their tendency to aggregate into plaques. High aggregate accumulation tendencies are particularly A [beta] (1-42) fragments, which are due to two very hydrophobic amino acid residues at its C-terminus. Thus, the A [beta] (1-42) fragment is believed to be primarily involved in the onset of neuroplastic formation in AD and is also considered essential, thus having a high pathological potential. Thus there is a need for specific molecules that can target and disperse amyloid plaque formation.

Symptoms of AD may be slow, and the first symptom may be mere amnesia. At this stage, the individual may forget the names of recent events, activities, acquaintances or things, and may not be able to solve simple math problems. As the disease progresses, symptoms become more easily recognized and become severe enough for a person with AD or a member of his family to seek medical help. Symptoms in the middle stages of AD include forgetting how to do simple things like grooming, and problems occur in speaking, understanding, reading, or writing. Later stage AD patients may become anxious or aggressive, lose their homes and eventually require comprehensive care.

Currently, the only reliable way to diagnose AD is to identify plaques and tangles in brain tissue at autopsy post mortality. Thus, while a person is still alive, the doctor can only perform a diagnosis of "possible" or "probable" AD. Using current methods, physicians can diagnose AD with less than 90 percent accuracy using a variety of tools to diagnose "potent" AD. The physician questions the person's overall health, past medical problems, and the history of all the difficulties that he or she has with performing daily activities. Memory, problem solving, concentration, calculation, and verbal behavioral tests provide information on cognitive degeneration, and medical tests such as tests of blood, urine, or spinal fluid and brain scans can provide some additional information.

Management of AD consists of dosing-based and non-dosing based therapies. Treatments aimed at changing the underlying process of the disease (delay or regression) have largely failed. Drugs that restore the deficiency (defect) or malfunctioning of chemical messengers (neurotransmitters) of nerve cells, especially cholinesterase inhibitors (ChEI) such as tacrine and rivastigmine Has been shown to improve symptoms. ChEI interferes with the enzymatic breakdown of neurotransmitters, increasing the amount of chemical messengers that can transmit nerve signals in the brain.

Tacrine (COGNEX ^® , Morris Plains, NJ), donepezil (ARICEPT ^® , drugs) for some people in the early and middle stages of the disease Tokyo, JP), rivastigmine (EXELON ^® , East Hanover, NJ), or galantamine (REMINYL ^® , New Brunswick, NJ) may help prevent some symptoms from worsening for a limited time. Another drug, memantine (NAMENDA ^® , New York, NY) was approved for the treatment of moderate to severe AD. Dosing can also address psychopathic manifestations of AD. In addition, some medications may help control the behavioral symptoms of AD such as insomnia, nervousness, wandering, anxiety and depression. Treatment of these symptoms often makes the patient more comfortable and also makes care easier for the caregiver. Unfortunately, although significant progress has been made in the treatment of this class of agents being consistently better than placebo, the disease continues to progress and the mean effect of mental function is not that great. For example, many drugs used in AD medications, such as ChEI, also have side effects including gastrointestinal dysfunction, liver toxicity, and weight loss.

Other diseases based on or related to the accumulation and deposition of amyloid-like proteins include mild cognitive impairment (MCI), Lewy small dementia (LBD), muscular dystrophy (ALS), inclusion body myositis (IBM) and macular degeneration, especially age There is related macular degeneration (AMD).

Mild cognitive impairment (MCI) is a general term most commonly defined as a subtle but measurable memory disorder. People with MCI experience larger memory problems than would normally be expected with aging, but they do not show other symptoms of dementia, such as judgments or impairment of reason.

Lewy body dementia (LBD) is a neurodegenerative disorder that can occur in people 65 years of age and older, which typically results in symptoms of cognitive (accident) disorders and abnormal behavioral changes. Symptoms may include cognitive impairment, neurological sign, sleep disorder, and autonomic failure. Cognitive impairment is a typical feature of LBD in most cases. Patients have recurrent episodes of confusion that are progressively worsening. The ups and downs of cognitive ability are often associated with changes in the level of attention and arousal. The ups and downs of cognitive impairment and thinking can change for minutes, hours, or days.

Atrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons. In some ALS patients, dementia or aphasia may appear (ALS-D). Dementia is most commonly anterior temporal dementia (FTD) and many of these cases have ubiquitin-positive, tau-negative inclusions in the frontal and temporal lobe surface layers and neurons of the dentate gyrus.

Inclusion body myositis (IBM) is a largely damaging disease commonly found in people over 50 years of age, and inflammation and progression of muscle fibers begin to shrink-the brain is not damaged, and patients maintain their complete thinking skills. . Two enzymes involved in the production of amyloid-β protein have been found to increase in muscle cells of patients with this most common progressive muscle disease in the elderly, and amyloid-β is also increased.

Macular degeneration is a common ocular disease that causes deterioration of the macula, the central area of the retina (a paper-like tissue behind the eye where light-sensitive cells send visual signals to the brain). A sharp, clear, 'straight ahead' vision is managed by the macula. Damage to the macula causes blind spots and blurring or astigmatism. Age-related macular degeneration (AMD) is the leading cause of visual impairment in people over 65 years of age in the United States, and the leading cause of legal blindness among whites. About 1.8 million Americans over 40 have advanced AMD, and another 8.3 million people with intermediate AMD are at real risk of vision loss. The government estimates that by 2020, 2.9 million people will have AMD. The victims of AMD are often surprised and frustrated to discover that there is little known about the treatment and causes of this blinding condition.

Macular degeneration is of two forms: dry macular degeneration and wet macular degeneration. The dry form, where the cells of the macular begin to slowly break down, is diagnosed in 85 percent of macular degeneration cases. One eye may lose sight and the other eye may remain intact, but both eyes typically have AMD. Drusen, a yellow deposit under the retina, is a common early sign of dry AMD. The risk of developing advanced dry or wet AMD increases as the size or number of drusen increases. Dry AMD can progress and cause vision loss without changing to the wet form of the disease; However, it is also possible that early-stage dry AMD suddenly changes to a wet form.

The wet form, although only accounting for 15 percent of cases, causes 90 percent of blindness and is considered advanced AMD (no early or mid-term phase of wet AMD). Habitual AMD is always preceded by dry-type disease. When the dry form deteriorates, some people begin to develop abnormal blood vessels behind the macula. These blood vessels are so fragile that fluid and blood leak (thus, 'wet' macular degeneration), which leads to rapid damage to the macula.

The dry form of AMD will often cause some blurring at first. Afterwards, the center of vision becomes blurred, especially as the disease progresses, the area becomes larger. If you have only one eye, you may not notice any symptoms. In hibernating AMD, a straight line may appear to be wavy and a loss of central vision may occur rapidly.

Diagnosis of macular degeneration usually involves looking at the back of the eye using a procedure called a dilated eye exam, a visual acuity test, and a fundoscopy to aid in the diagnosis of AMD. In addition, fluorescein angiography can be performed-if wet AMD is suspected. If dry AMD has reached advanced stages, there is no common treatment available to prevent vision loss. However, certain high dose formulations of antioxidants and zinc may delay or prevent progression of intermediate AMD to advanced stages. Macugen® (pegaptanib sodium injection), laser photocoagulation, and photodynamic therapy can control abnormal blood vessel growth and bleeding in the macula, which is wet Helpful for some people with AMD; However, vision lost already will not be recovered by these techniques. If vision is already lost, existing low vision aids can help to improve the quality of life.

One of the first signs of age-related macular degeneration (AMD) is the extracellular deposition known as drusen between the Bruch's membrane (BM) and the basal lamina of the retinal pigmented epithelium (RPE). Accumulation of water. Recent studies conducted by Anderson et al. Confirmed that drusen contains amyloid beta. (Experimental Eye Research 78 (2004) 243-256).

Prions cause neurodegenerative diseases such as scurvy of sheep, bovine bovine encephalopathy and human Creutzfeldt Jakob disease. The only known component of this particle is PrPSc, a scrappy isoform of the protein. Although prions are proliferating, there is no evidence that they retain nucleic acids. PrPSc is induced from non-infectious cellular protein PrPC by a posttranslational process during which PrPC undergoes profound conformational changes.

The scrapie protein PrPSc plays a crucial role in neurodegeneration and undergoes three stages of transition during disease progression: PrPC (the normal intracellular isoform of protein) - PrPSc: the form of infection (scrappy isoform of protein) - protein PrP27-30.

Such a series of events may be used to treat a variety of conditions including, but not limited to, Creutzfeldt Jakob Disease (CJD), rickets (Kuru), Gerstmann-Schlüsler-Shinker syndrome (GSS), male fatal familial insomnia, scorpions of sheep and goats, The bovine digestion occurs during the course of the encephalopathy.

The cell's non-toxic protein (PrPC) is a sialolycoprotein with a molecular weight of 33000 to 35000 which is mainly expressed in neurons. In the diseases mentioned above, PrPC is converted to its modified form (PrPSc), which is distinguishable from its normal homologue by its relative resistance to protease digestion. PrPSc accumulates in the central nervous system of infected animals and individuals, and the protease-resistant core aggregates extracellularly.

Amyloidosis is not a single disease entity but rather is characterized by extracellular tissue deposits of waxy, starch-like proteins called amyloid, which accumulate in one or more organs or bodies It is a diverse group of progressive disease processes. As the amyloid deposits accumulate, it begins to interfere with the normal functioning of the organ or body. There are at least 15 different types of amyloidosis. The main forms are primary amyloidosis without known antecedents, secondary amyloidosis following some other conditions, and hereditary amyloidosis.

Secondary amyloidosis is defined as tuberculosis, bacterial infections, which are called familial Mediterranean fever, bone infections (osteomyelitis), rheumatoid arthritis, small bowel (granulomatous ileitis) Hodgkin's disease, and leprosy, or those with inflammatory diseases.

Glaucoma is a characteristic pattern of optic neuropathy that is a group of optic nerve diseases associated with loss of retinal ganglion cells (RGCs). Glaucoma is not always the case, but is often accompanied by an increase in intraocular pressure, which may be the result of circulation of the aqueous fluid, or blockage of its excretion.

Although increased intraocular pressure is a significant risk factor for glaucoma progression, no threshold of definitive intraocular pressure can be defined to induce glaucoma.

Also, damage can be caused by poor blood supply to the major optic nerve fibers, weakening of the nerve structure, and / or health problems of the nerve fibers themselves.

Untreated glaucoma leads to permanent damage to the optic nerve and consequent visual field loss, which can lead to blindness.

RGC is a neuron that transmits visual signals from the eye to the brain. Caspase-3 and caspase-8 are two major enzymes in the apoptotic process and are activated in the process leading to RGC apoptosis. Caspase-3 degrades the amyloid precursor protein (APP) to produce a neurotoxic fragment containing amyloid beta. Without protective effects of APP, amyloid beta accumulation in the retinal ganglion cell layer results in the death of RGC and irreversible visual loss.

Different types of glaucoma are classified as closed-angle glaucoma when the condition is chronic, open-angle glaucoma, or when acute glaucoma occurs suddenly. Glaucoma usually affects both eyes, but this disease can progress more quickly than one eye.

Chronic open angle glaucoma (COAG), also known as primary open angle glaucoma (POAG), is the most common type of glaucoma. COAG is caused by microblocking in the trabecular meshwork, which reduces the discharge of aqueous liquor outflows to Schlemm's canal and increases intraocular pressure (IOP). POAG usually affects both eyes and is deeply related to age and positive family history. As the aging process causes gradual clogging of the eye's exhaust mechanism, the frequency increases in older people. The increase in IOP in subjects with chronic open angle glaucoma is not accompanied by any symptoms until I feel a loss in the central visual field.

Acute Angle Closure Glaucoma (AACG) or occlusion angle glaucoma is a relatively rare type of glaucoma characterized by a sudden increase in intraocular pressure from 35 to 80 mmHg, leading to severe pain and irreversible visual loss . The sudden increase in pressure is caused by blockage of the exhaust channel and clogging of the filtering angle. Individuals with narrow angles are at high risk for sudden closure of the angle. AACG usually occurs in one eye, but the risk is in both eyes. Age, cataracts, and pseudoexfoliation are also risk factors, because they are associated with angular dilation or enlargement and enlargement of the lens. Sudden onset of glaucoma can be associated with severe pain and headache, red eyes, nausea, vomiting, and blurred vision.

Mixed or combined mechanisms Glaucoma is a combination or combination of open angle or closed angle glaucoma. This is because patients with acute ACG who require angiographic treatment for IOP control open their angles after laser iris incision, as well as patients who have progressive narrowing of angular glaucoma or POAG, .

Normal tension glaucoma (NTG), also known as hypotonic glaucoma (LTG), is characterized by loss of peripheral vision and progressive optic nerve damage similar to that seen with other types of glaucoma; The intraocular pressure is in the normal range or even lower than normal.

Congenital (infant) glaucoma is a relatively rare, genetically open-angle glaucoma. Inadequate development of the exit area leads to an increase in eye pressure that can result in loss of vision from the optic nerve damage and enlarged eye. Early diagnosis and treatment are essential to preserve the sight of infants and young children with this disease.

Secondary glaucoma can be caused by eye damage, inflammation in the iris of the eye (iritis), diabetes, cataracts, or steroid use in steroid-sensitive individuals. Secondary glaucoma may also be associated with retinal detachment or retinal vein occlusion or occlusion.

Pigment glaucoma is characterized by the detachment of pigment granules from the iris. These granules cause occlusion of the eye's exhaust system, resulting in elevated intraocular pressure and damage to the optic nerve.

Glaucoma is a characteristic feature of the deposition of flaky material in the anterior capsule of the eye. Accumulation of sculptural material blocks the evacuation system and raises the intraocular pressure.

Diagnosis of glaucoma can be made using various tests. Tonomometry measures the pressure of the eye by measuring the tone or hardness of its surface. Some types of tonometers are available for such testing, the most common being application tonometrics. Corneal pachymetry measures the thickness of the cornea, followed by intraocular pressure. Anterior gonioscopy enables examination of the eye's exit area and filtering angle. Anterior cruciate goniometry can also measure whether abnormal blood pressure is blocking the discharge of aqueous fluid from the eye. Ophthalmoscopy enables the examination of the optic nerve and can detect changes in the optic disc or nerve fiber layer, or indentation (depression) of this structure, which can be caused by increased intraocular pressure or by axonal drop out . Anterior cruciate gonioscopy is also useful for assessing damage to the nerve from increased intraocular pressure or insufficient blood flow. The field of view can measure the field of view and, subjectively, it can detect signs of glaucomatous damage to the optic nerve. This is indicated by the specific pattern of field loss. Ocular coherence tomography, an objective measure of nerve fiber layer loss, is performed by examining the thickness of the optic nerve fiber layer (deformed in glaucoma) through differential transmission of light through the damaged axon tissue .

Optic nerve drusen is a globular concretion of calcium salts and proteins that are thought to represent secretions through the innately deformed vascular structures affecting the axon nerve fiber layer. These accumulations are believed to occur in the peripapillary nerve fiber layer and indirectly damage the nerve fiber layer by compression, either directly or through rupture of the vascular supply to the nerve fiber layer. They usually become observable after the first decade of the life of the diseased individual. They occur most frequently in both eyes, but can also be sick with only one eye, and may cause a loss of mild peripheral vision over the years.

Visual neuropathy is a disease characterized by demyelination of the horse, occlusion of the blood supply, malnutrition, or damage to the optic nerve caused by toxins. Dislocated optic neuropathy (see optic neuritis below) is typically triggered by a spinal cord dropout process, such as multiple sclerosis. Obstruction of the blood supply, known as ischemic optic neuropathy, can result in dysfunction or death of optic nerve cells. Non-arterial ischemic optic neuropathy predominates in the middle-aged. Risk factors include hypertension, diabetes, and atherosclerosis. Arteritis Ischemic optic neuropathy is common in older people after inflammation of the arteries (arteritis), especially inflammation of the coronary arteries (temple arteritis). Visual loss can be rapid, or can progress gradually over 2-7 days, and damage can be given to either one eye or both eyes. In people with visual neuropathy caused by exposure to toxins or malnutrition, both eyes are usually injured.

About 40% of people with non-arterial ischemic optic neuropathy experience spontaneous improvement over time. Non-arterial ischemic optic neuropathy is treated by controlling blood pressure, diabetes and cholesterol levels. Arterial ischemic optic neuropathy is treated with a high dose of corticosteroids to prevent vision loss in the second eye.

Optic neuritis is associated with mild or severe visual loss in one or both eyes and is caused by systemic hippocampal detachment processes (see above), viral infection, vaccination, meningitis, syphilis, multiple sclerosis and intraocular inflammation (uveitis) . Eye movement can be painful, and vision can get worse with repeated episodes. Diagnosis involves examining the pupil's response and determining whether the optic nerve papilla is swollen. Magnetic resonance imaging (MRI) can show evidence of multiple sclerosis or, rarely, tumors that compress the optic nerve, in which case the vision is improved once the tumor pressure is relieved. Most of the optic neuritis improves over a few months without treatment. In some cases, treatment with intravenous corticosteroids may be necessary.

Cataract is a clouding that proceeds from the lens of the eye or from its skin. Cataracts usually cause progressive visual loss and can cause blindness if left untreated. In Morgagnian cataracts, the cataract cortex gradually becomes liquefied to form a milky white fluid, which can cause severe irritation if the lens capsule ruptures and leaks. If left untreated, this cataract can also cause lens-blind glaucoma. Cataracts are either inherently inherited or can be caused by genetic factors, aging, long-term ultraviolet exposure, radiation exposure, diabetes, eye damage or physical trauma.

Extracapsular (ECCE) surgery is the most effective treatment for cataracts. In this procedure, the lens is removed, but most of the lens capsule remains intact. Phacoemulsification, a small incision on the side of the cornea, is commonly used to break up the lens before extraction.

Ocular amyloidosis is a genetic disorder associated with Type I familial amyloidotic polyneuropathy (FAP), abnormal conjunctival vessels, dry keratoconjunctivitis, pupillary abnormalities and, in some cases, vitreous clouding and secondary glaucoma. It is characterized by. Type 1 FAP is associated with mutations in the serum plasmid (prealbumin) synthesized in the liver, retinal pigment epithelium 2, brain parenchyma, and trans-tritectin (TTR). Different mutations cause transtyretin to polymerize into the pleated structure of amyloid fibrils, leading to genetic amyloidosis. The most frequent mutation is TTR-met303, where methionine replaces valine at position 30 of transtyretin.

Type 4 FAP is associated with lattice keratopathy (LCD). Grid corneal dystrophy is a hereditary, primary, and usually bilateral corneal amyloidosis characterized by the presence of a refractile lattice line with dual contours in the corneal stroma. The Type 1 LCD displays normal chromosomal dominance, bilateral symmetry characterized by the presence of numerous transparent fine grid lines with faint haze and white dots on the surface of the (Biber-Haab-Dimmer) It is a red corneal disorder. Symptoms start during the first or second decade of life and cause progressive vision loss. Most patients require corneal transplants for up to 40 years. Type 2 LCD is associated with systemic amyloidosis (Meretoja's syndrome) and is characterized by the presence of thick lattice lines in the limbus, central cornea, and striae. Vision is not affected until the end of life. Type III LCDs affect people in the middle-aged and are characterized by the presence of a thick grid line extending from the edge to the edge. Type 3A LCDs are characterized by the accumulation of amyloid deposits in the plaques and the presence of ribbons between the plaques and Bowman's layer and because of the presence of corneal erosion, white development and autosomal dominant dielectric patterns The type LCD is different from the type 3 LCD.

Down syndrome (DS) or 21-year-old trisomy is the most common genetic disorder with a frequency of about 1: 700 survival births, often associated with various congenital malformations. This disorder, which is caused by the presence of extra chromosome 21, is associated with premature deposition of plaque-forming protein amyloid-beta and progression of Alzheimer's disease to middle age. In addition, many people with DS suffer from cataracts that originate from childhood, and many suffer from congenital glaucoma. Because the gene for the amyloid precursor protein, which is degraded to form amyloid beta, is located on the long arm of chromosome 21 in humans, overexpression of this gene is associated with increased levels of amyloid precursor protein and amyloid precursor protein in Down's syndrome It can lead to sedation.

There is no cure for glaucoma. Drug treatments for the treatment of glaucoma include agents that reduce the production of aqueous humor in the eye such as beta-blockers (Timoptic, Betoptic), carbonic anhydrase inhibitors (Trusopt, Azopt), and alpha agonists (Alphagan, Iopidine ), And an agent that turns the direction of discharge of the ocular waterproofing through a different path in the back of the eye, such as prostaglandin (Xalatan). Laser surgery involves trabeculoplasty, a procedure that helps the eye waterproof to be released more efficiently from the eye. According to the Glaucoma Foundation, nearly 80% of patients respond well to the process of delaying or avoiding additional surgery. However, according to the National Eye Institute, the pressure increases again in half the eyes of all patients within two years after laser surgery. If medication and initial laser treatment are not successful in reducing pressure in the eye, an incision surgery is performed. One type of surgery, trabeculotomy, creates an opening in the wall of the eye to allow drainage of the eye waterproof. However, according to the Glaucoma Association, about one third of trabeculoplasty patients undergo cataracts within five years. If the fiber incision fails, the additional incision procedure involves placing the tube in the eye between the cornea and the iris, and using the laser or freezing to destroy the tissue of the eye that makes the eye waterproof. Surgery can maintain the patient's remaining vision, but does not improve vision. Vision may actually get worse after surgery.

Age-related macular degeneration (AMD) is the leading cause of blindness among white people over 65 years of age. Although much progress has been made in the study of macular degeneration until recently, there is no treatment to relieve neuronal apoptosis that occurs during the course of the disease. There is also no clear treatment for other eye diseases associated with amyloid beta-related neuronal degradation, such as cortical visual deficits, optic nerve drusen, optic neuropathy, optic neuritis, amyotrophy and lattice dystrophy.

Amyloid deposits typically contain three components. The amyloid protein fibril, which comprises about 90% of the amyloid material, includes one of several different types of proteins. These proteins are folded into so-called "beta-pleated" sheet fibrils, a unique protein configuration that represents a binding site for Congo red, which causes the unique staining properties of amyloid protein. Can be. Amyloid deposits also contain amyloid P (pentagonal) component (AP), glycoproteins involved in normal serum amyloid P (SAP), and sulfated glycosaminoglycan (GAG), a complex carbohydrate of connective tissue. Include.

One development for the treatment of Alzheimer's disease and prion disease is the design of molecules that bind to abnormal β-sheet conformations of Aβ and PrP, respectively, to prevent aggregation of these molecules. The β-sheet conformation of peptides is characterized in that the hydrogen bonds are formed in a conventional pattern between neighboring amino acid strands. This arrangement results in a stable three-dimensional structure. H-binding receptors (C═O groups) and H-binding donors (NH groups) alternate in naturally occurring β-sheet peptides with molecules that are approximately bound in one line. Within each amino acid strand, the distance between neighboring H-binding donors and H-binding receptors is within a certain range. In particular, the distance between the H-binding donor (NH group) and the H-binding receptor (C═O group) within one amino acid residue is between 3.5 and 4.0 mm 3. The distance between the H-binding receptor (C═O group) of one amino acid residue and the H-binding donor (NH group) of the next amino acid residue involved in inter-strand bonding is 2.6 to 2.9 mm 3. In other words, the distance between neighboring H-binding donors and H-binding receptors within an amino acid strand is alternating within the following ranges.

H-bond donor (amino acid 1) - H-bond receptor (amino acid I) = 3.5-4.0 A

H-binding receptor (amino acid 1) -H-binding donor 2 (amino acid 2) = 2.6-2.9 kPa

The ligands designed to bind to the? -sheet ideally have an order of H-bonding donors and H-bonding receptors that are complementary to the order of H-bonding donors and H-bonding receptors in the amino acid strand of the? -sheet.

WO 2007/002433 describes certain pyrrolo [2,3-B] pyridine derivatives which are described as suitable as protein kinase inhibitors.

It is an object of the present invention to provide compounds which can be used for the treatment of diseases or conditions associated with amyloid or amyloid-like proteins, such as amyloidosis. These compounds must be able to pass through the blood-brain barrier. In addition, they must be pharmaceutically acceptable and in particular they should not be highly susceptible to mutations, or be carcinogenic or metabolically unstable.

A further object of the present invention is to provide a subject with an ocular disease associated with pathological abnormalities / changes of visual tissue, in particular amyloid-beta-related pathological abnormalities / changes of visual tissue, such as, for example, neurolysis. To provide improved treatment options. Such pathological abnormalities include, for example, visual cortex resulting in cortical visual deficit; Optic nerve and anterior chamber that bring glaucoma; A lens that causes cataracts due to beta-amyloid deposition; A vitreous body that causes amyloidosis; Primary retinal degeneration and macular degeneration, such as retinas resulting in age-related macular degeneration; Optic nerve drusen, optic neuropathy that causes optic neuropathy and optic neuritis; And lattice dystrophy in the cornea of the eye.

The inventors have surprisingly found that these objects can be achieved by the compounds of general formula (I) which are described in detail below.

The present invention therefore relates to compounds of general formula (I).

In a further aspect, the present invention relates to a pharmaceutical composition or radiopharmaceutical formulation comprising a compound of formula (I).

A further aspect of the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease or condition associated with an amyloid or amyloid-like protein, including amyloidosis.

Also described herein are methods of treating a disease or condition associated with an amyloid or amyloid-like protein, comprising administering to a subject in need thereof an effective amount of a compound of formula (I).

Another aspect of the present invention relates to the use of a compound of formula (I) for the manufacture of a medicament for reducing or treating the effects of eye diseases associated with pathological abnormalities / changes in visual tissue.

Also included herein are methods for alleviating or treating the effects of eye diseases associated with pathological abnormalities / changes in tissues of the visual system, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) It is described.

Eye diseases associated with pathological abnormalities / changes in tissues of the visual system are particularly associated with amyloid-beta-related pathological abnormalities / changes in tissues of the visual system, such as, for example, neurolysis. Such pathological abnormalities include, for example, visual cortex resulting in cortical visual deficit; Optic nerve and anterior chamber that bring glaucoma; A lens that causes cataracts due to beta-amyloid deposition; A vitreous body that causes amyloidosis; Primary retinal degeneration and macular degeneration, such as retinas resulting in age-related macular degeneration; Optic nerve drusen, optic neuropathy that causes optic neuropathy and optic neuritis; And lattice dystrophy in the cornea of the eye.

In a further aspect, the invention relates to a pharmaceutical composition comprising a compound according to the invention and optionally at least one additional biologically active compound and / or a pharmaceutically acceptable carrier and / or diluent and / or excipient. ). ≪ / RTI > The additional biologically active substance may be selected from the group of diseases and disorders associated with amyloid or amyloid-like proteins, such as A [beta] proteins associated with Alzheimer's disease, diseases or disorders associated with or caused by amyloid or amyloid- May be a known compound used for drug treatment.

Said additional biologically active substance or compound may exert its biological effect by a mechanism the same or similar to a compound according to the invention, or by an irrelevant mechanism of action, or by a combination of related and / or unrelated mechanism of action.

Methods for collecting data for the diagnosis of an amyloid-related disease or condition in a sample or patient are also described, including:

(a) contacting a sample suspected of containing an amyloid protein or a specific bodily area or bodily area with a compound according to the present invention

(b) allowing the compound to bind to the amyloid protein;

(c) detecting a compound attached to the protein; And

(d) optionally correlating the presence or absence of a compound bound to the amyloid protein with the presence or absence of an amyloid protein in the sample or a specific body part or body region.

A further embodiment of the invention is a method of measuring the degree of amyloidogenic plaque burden in tissues and / or body fluids comprising:

(a) providing a sample representative of the tissue and / or body fluid under investigation;

(b) testing the sample for the presence of an amyloid protein with a compound according to the present invention;

(c) measuring the amount of the compound bound to the amyloid protein; And

(d) calculating plaque load in the tissue and / or body fluid.

A further aspect of the sample within, or in-situ (in situ) amyloid in a patient comprising detecting the specific binding of the compounds according to the invention for amyloid protein in - measuring the stamp (predisposition) for the relevant disease or condition A method of gathering data for: comprising the following steps:

(a) contacting a sample suspected of containing an amyloid protein or a particular body region or body region with a compound according to the present invention, wherein said compound specifically binds to said amyloid protein;

(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;

(c) detecting the formation of said compound / protein complex;

(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And

(e) optionally comparing the amount of compound / protein complex to a normal control value.

A further aspect of the invention is a method of collecting data for monitoring minimal residual disease in a patient after treatment with an antibody or vaccine composition, the method comprising:

(a) contacting a sample suspected of containing an amyloid protein or a specific body region or body region with a compound according to the present invention, wherein said compound specifically binds to an amyloid protein;

(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;

(c) detecting the formation of said compound / protein complex;

(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And

(e) optionally comparing the amount of compound / protein complex to a normal control value.

Methods for collecting data for predicting the responsiveness of a patient being treated with an antibody or vaccine composition are also described, including:

(a) contacting a sample suspected of containing an amyloid protein or a specific body region or body region with a compound according to the present invention, wherein said compound specifically binds to an amyloid protein;

(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;

(c) detecting the formation of said compound / protein complex;

(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And

(e) optionally comparing the amount of compound / protein complex to a normal control value.

A further aspect of the invention is a test kit for the detection and diagnosis of amyloid-related diseases or conditions, comprising a compound according to the invention.

In another aspect of the invention, the compounds according to the invention are for use in inhibiting protein aggregation, in particular for inhibiting Aβ _1-42 aggregation, tau aggregation or alpha-synuclein aggregation.

In one aspect of the invention, the use of a compound according to the invention comprises (a) reducing the β-amyloid plaque load and / or (b) inhibiting the formation of β-amyloid plaques and / or (c) in the brain of a patient The manufacture of a medicament for delaying the increase in amyloid rods is described.

A further embodiment of the invention comprises (a) reducing the β-amyloid plaque load, and / or (b) the β-amyloid plaque, comprising administering an effective amount of a compound according to the invention to a subject in need thereof. To inhibit the formation of and / or (c) delay the increase in amyloid load in the brain of the patient.

In another embodiment, the compounds according to the invention comprise (a) reducing the β-amyloid plaque load, and / or (b) inhibiting the formation of β-amyloid plaques, and / or (c) the amyloid rod in the brain of the patient. It is intended to be used to delay the increase of.

According to a further aspect, the present invention relates to the use of a compound according to the invention for the preparation of a medicament for maintaining or increasing the cognitive memory capacity of a subject suffering from memory impairment.

According to another aspect, the present invention provides a method for maintaining or increasing the cognitive memory capacity of a subject suffering from a memory disorder, comprising administering to a subject in need thereof an effective amount of a compound according to the invention.

Another aspect of the invention relates to a compound according to the invention for use in maintaining or increasing the cognitive memory capacity of a subject suffering from a memory disorder.

Preferred embodiments of the invention are described in the dependent claims.

Individual compounds known from WO 2007/002433 are not within the scope of the present invention with respect to compounds or pharmaceutical compositions. Such compounds are listed below, for example.

Such compounds may be included in the scope of other claims or may be excluded from the scope of other claims. The compounds may be excluded alone, in combination of two or more, or all of the compounds may be excluded from any other claims.

1 shows quantification of cortex (a and b) and hippocampus (c and d) 6E10 immunofluorescence.
In FIGS. 2A and 2B, APPV171I transgenic mice treated with PBS and ACI-636 were analyzed.
FIG. 3 shows the separation of Boc-protected precursors of Compound 26 by chiral HPLC.
4 shows the initial enantiomers after separation.
5 shows the terminal enantiomers after separation.
6 shows the racemic mixture before crystallization.
FIG. 7 shows the initial eluting enantiomer A (dihydrochloride salt) after crystallization.
8 shows the late eluted enantiomer B (dihydrochloride salt) after crystallization.
9 depicts Boc-protected precursors of compound 214b derived from the terminal diastereomers.
FIG. 10 shows Boc-protected precursor of 214a derived from the initial diastereomer.
FIG. 11 shows ¹ H-NMR data of the initial diastereomers (aromatic regions only, impurities present in regions 7.1-7.3 ppm).
FIG. 12 depicts ¹ H-NMR data of the terminal diastereomers (aromatic regions only, impurities present in regions 7.1-7.3 ppm).

Justice

Within the meaning of the present invention, the following definitions apply:

"Alkyl" refers to a saturated organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and include methyl, ethyl, propyl and butyl.

"Cycloalkyl" refers to a cyclic organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 5 to 10 carbon atoms, preferably 5 to 6 carbon atoms, and include cyclopentyl and cyclohexyl.

"Heterocycloalkyl" means that one or more carbon atoms are replaced by a heteroatom, eg, a heteroatom selected from N, O or S, or a heteroatom (eg, N, O and / or S) -containing moiety. The cycloalkyl group as mentioned above is shown. Examples of possible heterocycloalkyl groups include pyrrolidine, tetrahydrofuran, piperidine, and the like.

"Alkenyl" refers to an organic moiety composed of carbon and hydrogen atoms comprising one or more double bonds. Examples of suitable alkenyl groups have 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and include propenyl and butenyl.

"Alkynyl" refers to an organic moiety consisting of carbon and hydrogen atoms containing one or more triple bonds. Examples of suitable alkynyl groups have 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and include propynyl and butynyl.

"Aryl" preferably denotes an aromatic organic moiety composed of carbon and hydrogen atoms having 5 to 10 carbon atoms, more preferably 5 or 6 carbon atoms. An example is the phenyl ring.

"Heteroaryl" means a tactic in which one or more carbon atoms are replaced by a heteroatom, eg, a heteroatom selected from N, O or S, or a heteroatom (eg, N, O and / or S) -containing moiety An aryl group as shown is shown. Examples of possible heteroaryl groups include pyridine and the like.

"Alkoxy" refers to the group -O-alkyl.

"Aminoalkyl" refers to the group alkyl-NR ¹ R ² .

"Hal" or "halogen" refers to F, Cl, Br, and I. Preferred Hal is F and Cl, more preferably F.

"Arylalkyl" refers to the group aryl-alkyl-.

"Cycloalkylalkyl" refers to the group cycloalkyl-alkyl-.

"Fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by fluoro atoms.

"Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms.

"Heteroarylalkyl" refers to the group heteroaryl-alkyl-.

"Heterocycloalkylalkyl" refers to the group heterocycloalkyl-alkyl-.

"Heteroatom-containing moieties" are, for example, moieties containing N, O and / or S. Examples of such moieties include -C (O)-, -C (O) O-, and -N (R ⁵⁰ )-, wherein R ⁵⁰ is, for each occurrence, R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (= NR ²⁰ ) NR ²¹ R ^a , C And independently selected from the group consisting of (= NOR ²⁰ ) R ²¹ and C (O) NR ²⁰ R ²¹ . Specific examples are -C (O) -, -C ( O) O- and -N (R ⁵⁰⁾ - and comprises a, in which R ⁵⁰ is from the group consisting of H or C _{1 -4} alkyl, for each occurrence Selected independently.

If the group is defined as being "optionally substituted", which Hal, C _{1 -6} alkyl, C _{1 -6} alkoxy, -SO ₂ - _{alkyl, -NH 2, -NH (C 1} -6 alkyl) or -N (C _1-6 alkyl) may have one or more substituents selected from the _second.

Compounds of the present invention having one or more optically active carbons include racemates and racemic mixtures, stereoisomers (diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of isomers and monomorphs) Isomers), tautomers, atropisomers, and rotamers (morphoisomers). All isomeric forms are included in the present invention. Compounds described herein that include olefinic double bonds include the E and Z geometric isomers. All salt forms, polymorphs, hydrates and solvates are also included in the present invention.

The solvent included in the solvate is not particularly limited and may be any pharmaceutically acceptable solvent. Examples include water and C _{1 -4} alcohol (e.g. methanol or ethanol).

Patients or subjects that can be treated with the present invention are typically animals, especially mammals, more particularly humans.

Preferred definitions given in the "Definitions" section apply to all embodiments described below unless stated otherwise.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a compound of formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates, and polymorps thereof.

A is selected from the group consisting of:

L ₁ is directionally selected from the group consisting of:

The term “directed” means that the bond shown on the left side of formula (a) and the two bonds shown on the left side of formula (b) are bonded to A, while the bond shown on the right side of formula (a) It means that the bond shown on the right side of b) is bonded to B. As will be readily apparent to those skilled in the art, formula (b) will only be combined with formula (vii) as an option of A. In a preferred embodiment L ₁ is (a).

B is selected from the group consisting of:

,

또는

)로부터 각각 독립적으로 선택된다. 보다 바람직하게는 R¹은 수소, F, CN, CF₃,

,

및

로부터 각각 독립적으로 선택된다.R ¹ is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , alkyl, -O-alkyl, -C (O) O-alkyl, cyclo Each independently selected from the group consisting of alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cyclo Alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl may be optionally substituted. In a preferred embodiment R ¹ is hydrogen, halogen (such as F), CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , -O-alkyl, heterocycloalkyl ( for example

,

or

Are each independently selected. More preferably R ¹ is hydrogen, F, CN, CF ₃ ,

,

And

Are each independently selected from.

,

또는

)로부터 각각 독립적으로 선택된다. 바람직한 구현예에서 R²는 수소, F, CN, CF₃, -CONR³⁰R³¹, -O-알킬,

,

및

로부터 각각 독립적으로 선택된다.R ² is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , alkyl, -O-alkyl, -C (O) O-alkyl, cyclo Each independently selected from the group consisting of alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cyclo Alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl may be optionally substituted. In a preferred embodiment R ² is hydrogen, halogen (such as F), CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , -O-alkyl, heterocycloalkyl ( for example

,

or

Are each independently selected. In a preferred embodiment R ² is hydrogen, F, CN, CF ₃ , -CONR ³⁰ R ³¹ , -O-alkyl,

,

And

Are each independently selected from.

,

또는

)로부터 각각 독립적으로 선택된다. 보다 바람직하게는 R³은 수소, F, -O-알킬, CF₃,

,

및

로부터 각각 독립적으로 선택된다.R ³ is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , alkyl, -O-alkyl, -C (O) O-alkyl, cyclo Each independently selected from the group consisting of alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cyclo Alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl may be optionally substituted. In a preferred embodiment R ³ is hydrogen, halogen (such as F), CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , -O-alkyl, heterocycloalkyl ( for example

,

or

Are each independently selected. More preferably R ³ is hydrogen, F, -O-alkyl, CF ₃ ,

,

And

Are each independently selected from.

,

또는

)로부터 각각 독립적으로 선택된다. 보다 바람직하게는 R⁴는 수소이다. R ⁴ is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , alkyl, -O-alkyl, -C (O) O-alkyl, cyclo Each independently selected from the group consisting of alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cyclo Alkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl may be optionally substituted. In a preferred embodiment R ⁴ is hydrogen, halogen (such as F), CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , -O-alkyl, heterocycloalkyl ( for example

,

or

Are each independently selected. More preferably R ⁴ is hydrogen.

에 의해 치환될 수 있다. 한 구현예에서 R¹ 및 R²는 합쳐져서 5- 내지 8-멤버의 탄소 원자를 함유하는 고리, 예컨대 6-멤버의 카르보사이클릭 고리를 형성할 수 있다. 상기 고리는 포화되거나 하나 이상의 이중 결합을 포함할 수 있다(방향족 고리를 포함함). 고리를 형성하는 기의 예는 -(CH₂)³- (즉, 포화된 5-멤버의 고리), -(CH₂)₄-, -O-(CH₂)-O-이다. 이들 고리는 임의로 치환될 수 있다.In further embodiments when any groups R ¹ / R ² / R ³ / R ⁴ are adjacent, they are optionally combined to form a carbon atom and optionally one or more heteroatoms or heteroatoms selected from O, S, or N (e.g. For example, it may form a ring of 5- to 8-members containing N, O and / or S) -containing moieties, wherein the ring of 5- to 8-members is NR ²⁰ R ²¹ or -O- May be substituted by alkyl, wherein said alkyl may be optionally substituted, or

It may be substituted by. In one embodiment, R ¹ and R ² can be combined to form a ring containing 5- to 8-membered carbon atoms, such as a 6-membered carbocyclic ring. The ring may be saturated or include one or more double bonds (including aromatic rings). Examples of groups forming a ring are — (CH ₂ ) ³ — (ie, a saturated 5-membered ring), — (CH ₂ ) ₄ —, —O— (CH ₂ ) —O—. These rings may be optionally substituted.

Examples of optional substituents on the 5- to 8-membered ring include -O-alkyl, -O-alkyl-Hal, -O-alkyl-O-alkyl, -NH-alkyl-O-alkyl, and -alkyl-SO ₂ alkyl.

R ^a is hydrogen, alkyl, haloalkyl, S (O) _t NR ³⁰ R ³¹ , S (O) _t R ³⁰ , C (O) OR ³⁰ , C (O) R ³⁰ , and C (O) NR ³⁰ R ^Are independently selected from the group consisting of ³¹ . In a preferred embodiment, R ^a is hydrogen or alkyl.

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted. In a preferred embodiment R ^b is hydrogen, halogen (such as F), CONR ³⁰ R ³¹ or alkyl.

For each occurrence R ²⁰ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and Independently selected from the group consisting of aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroaryl Alkyl and aminoalkyl may be optionally substituted. In a preferred embodiment R ²⁰ is hydrogen or alkyl.

For each occurrence R ²¹ is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, hetero Independently selected from the group consisting of arylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl , Heteroarylalkyl and aminoalkyl may be optionally substituted. In a preferred embodiment R ²¹ is hydrogen or alkyl.

In one embodiment R ²⁰ and R ²¹ are combined with the nitrogen to which they are attached to one or more additional heteroatoms or heteroatoms (eg, N, O and / or S) selected from a carbon atom and optionally O, S, or N May form a ring of 3- to 8-members containing a) -containing moiety, wherein the ring of 3- to 8-members may be optionally substituted. The ring may be saturated or include one or more double bonds (including aromatic rings). In one embodiment the ring is carbocyclic separate from the nitrogen atom to which R ²⁰ and R ²¹ are attached. In other embodiments, the ring contains one additional heteroatom (such as N or O) in addition to the nitrogen atom to which R ²⁰ and R ²¹ are attached.

For each occurrence R ³⁰ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and Independently selected from the group consisting of aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, hetero Arylalkyl and aminoalkyl may be optionally substituted. In a preferred embodiment R ³⁰ is hydrogen or alkyl.

For each occurrence R ³¹ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and Independently selected from the group consisting of aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, hetero Arylalkyl and aminoalkyl may be optionally substituted. In a preferred embodiment R ³¹ is hydrogen or alkyl.

When a nitrogen atom is present in the ring formed by R ¹ / R ² / R ³ / R ⁴ or in the ring formed by R ²⁰ and R ²¹ , it may be in any suitable form. Possible forms include -N (R ⁵⁰ )-, and -N =.

X is each independently selected from the group consisting of CR ^b and N.

Y is independently selected from the group consisting of CR ^b and N, respectively.

t is 1 or 2;

p is 0, 1 or 2; In one embodiment p is zero.

In a preferred embodiment A is selected from the group consisting of

이다. L ₁ is

to be.

B is selected from the group consisting of

Wherein R ¹ , R ² , R ³ , R ⁴ , R ^a , R ²⁰ , X and Y have the same meaning as above;

V is absent or NR ²⁰ R ²¹ ,

z is 1 or 2.

Combinations of any of the above definitions are also contemplated herein.

In one embodiment A has the formula (i):

를 포함한다. 한 바람직한 구현예에서 상기 식 (i)은

이다. 다른 바람직한 구현예에서 상기 식 (i)은

이다. Preferred embodiments of formula (i)

. In one preferred embodiment, Formula (i) is

to be. In another preferred embodiment Formula (i) is

to be.

In this embodiment, R ¹ , R ² , R ³ and R ^b are as described above.

In one embodiment A has the formula (ii):

,

또는

이고, 바람직하게는 R² 및 R^a는 수소이고, R¹은

또는

이다 .Preferred embodiments of formula (ii) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ And R ² is hydrogen, preferably R ¹ And R ² together form — (CH ₂ ) ₄ —. In alternative embodiments R ² and R ^a are hydrogen and R ¹ is

,

or

Is preferably R ² and R ^a are hydrogen, and R ¹ is

or

to be .

In one embodiment A has the formula (iii)

,

또는

이다. 한 바람직한 구현예에서 바람직하게는 R²는 수소이고, R¹은

또는

이다.Preferred embodiments of formula (iii) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ And R ² is hydrogen, or preferably R ² is hydrogen, R ¹ is

,

or

to be. In one preferred embodiment preferably R ² is hydrogen and R ¹ is

or

to be.

In one embodiment A has the formula (iv)

,

또는

이다. 한 바람직한 구현예에서 바람직하게는 R²는 수소이고, R¹은

또는

이다. Preferred embodiments of formula (iv) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ And R ² is hydrogen, or preferably R ² is hydrogen, R ¹ is

,

or

to be. In one preferred embodiment preferably R ² is hydrogen and R ¹ is

or

to be.

In one embodiment A has the formula (v)

,

또는

이다. 한 바람직한 구현예에서 바람직하게는 R²는 수소이고, R¹은

또는

이다. Preferred embodiments of formula (v) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ And R ² is hydrogen, or preferably R ² is hydrogen, R ¹ is

,

or

to be. In one preferred embodiment preferably R ² is hydrogen and R ¹ is

or

to be.

In one embodiment A has the formula (vi)

,

또는

이다. 한 바람직한 구현예에서 바람직하게는 R²는 수소이고, R¹은

또는

이다.Preferred embodiments of formula (vi) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ And R ² is hydrogen, or preferably R ² is hydrogen, R ¹ is

,

or

to be. In one preferred embodiment preferably R ² is hydrogen and R ¹ is

or

to be.

In one embodiment A has the formula (vii)

Preferred embodiments of formula (vii) include wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen. Further preferred embodiments of formula (vii) include the following.

In one embodiment A has the formula (viii).

Preferred embodiments of formula (viii) include those wherein R ³ is F and R ^a is hydrogen or R ³ and R ^a are hydrogen.

In one embodiment L 1 has the formula (a) below.

바람직한 구현예에서 p = 0이다.

In a preferred embodiment p = 0.

In one embodiment B has the formula (ix)

,

또는

이고; 보다 보람직하게는 CN,

,

이다), R²는 수소이다. 추가의 바람직한 구현예에서 R¹ 및 R²는 임의로 치환된 고리를 형성할 수 있다. 고리를 형성하는 R¹ 및 R²의 예는 임의로 치환될 수 있는 -(CH₂)₃- 및 -(CH₂)₄- 이다. Preferred embodiments of formula (ix) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ And R ² is hydrogen. In a further preferred embodiment of the, R ¹ are as defined in the above-mentioned general definitions (e.g. CN, -COO (C _{1 -4} alkyl),

,

or

ego; More advantageously CN,

,

R ² is hydrogen. In further preferred embodiments R ¹ and R ² may form an optionally substituted ring. Examples of R ¹ and R ² forming a ring are — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ — which may be optionally substituted.

In one embodiment B has the formula (x):

,

,

이고; 보다 보람직하게는 CN,

,

이다), R²는 수소이다. 추가의 바람직한 구현예에서 R¹ 및 R²는 임의로 치환된 고리를 형성할 수 있다. 고리를 형성하는 R¹ 및 R²의 예는 임의로 치환될 수 있는 -(CH₂)₃- 및 -(CH₂)₄- 이다. Preferred embodiments of formula (x) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ and R ² are hydrogen. In a further preferred embodiment of the, R ¹ are as defined in the above-mentioned general definitions (e.g. CN, -COO (C _{1 -4} alkyl),

,

,

ego; More advantageously CN,

,

R ² is hydrogen. In further preferred embodiments R ¹ and R ² may form an optionally substituted ring. Examples of R ¹ and R ² forming a ring are — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ — which may be optionally substituted.

In one embodiment B has the formula (xi)

,

,

이고; 보다 보람직하게는 CN,

,

이다), R²는 수소이다. 추가의 바람직한 구현예에서 R¹ 및 R²는 임의로 치환된 고리를 형성할 수 있다. 고리를 형성하는 R¹ 및 R²의 예는 임의로 치환될 수 있는 -(CH₂)₃- 및 -(CH₂)₄- 이다. Preferred embodiments of formula (xi) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ and R ² are hydrogen. In a further preferred embodiment of the, R ¹ are as defined in the above-mentioned general definitions (e.g. CN, -COO (C _{1 -4} alkyl),

,

,

ego; More advantageously CN,

,

R ² is hydrogen. In further preferred embodiments R ¹ and R ² may form an optionally substituted ring. Examples of R ¹ and R ² forming a ring are — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ — which may be optionally substituted.

In one embodiment B has the formula (xii).

,

,

이고; 보다 보람직하게는 CN,

,

이다), R²는 수소이다. 추가의 바람직한 구현예에서 R¹ 및 R²는 임의로 치환된 고리를 형성할 수 있다. 고리를 형성하는 R¹ 및 R²의 예는 임의로 치환될 수 있는 -(CH₂)₃- 및 -(CH₂)₄- 이다. Preferred embodiments of formula (xii) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ and R ² are hydrogen. In a further preferred embodiment of the, R ¹ are as defined in the above-mentioned general definitions (e.g. CN, -COO (C _{1 -4} alkyl),

,

,

ego; More advantageously CN,

,

R ² is hydrogen. In further preferred embodiments R ¹ and R ² may form an optionally substituted ring. Examples of R ¹ and R ² forming a ring are — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ — which may be optionally substituted.

In one embodiment B has the formula (xiii).

,

,

이고; 보다 보람직하게는 CN,

,

이다), R²는 수소이다. 추가의 바람직한 구현예에서 R¹ 및 R²는 임의로 치환된 고리를 형성할 수 있다. 고리를 형성하는 R¹ 및 R²의 예는 임의로 치환될 수 있는 -(CH₂)₃- 및 -(CH₂)₄- 이다. Preferred embodiments of formula (xiii) include those R ^a is hydrogen or C _{1 -4} alkyl. In a further preferred embodiment R ¹ and R ² are hydrogen. In a further preferred embodiment of the, R ¹ are as defined in the above-mentioned general definitions (e.g. CN, -COO (C _{1 -4} alkyl),

,

,

ego; More advantageously CN,

,

R ² is hydrogen. In further preferred embodiments R ¹ and R ² may form an optionally substituted ring. Examples of R ¹ and R ² forming a ring are — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ — which may be optionally substituted.

In one embodiment, the compounds of the present invention are preferably of the following formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof:

here,

이고, A is

ego,

이고, L ₁ is

ego,

B is

또는

이고,

or

ego,

here,

R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl Each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl May be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;

R < ³ > is hydrogen or halogen;

R ^a is hydrogen or alkyl;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;

Each Y is independently CH or N;

t is 1 or 2;

z is 1 or 2.

In a further embodiment, the compounds of the invention are preferably of the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof:

here,

이고, A is

ego,

이고, L ₁ is

ego,

이고, B is

ego,

here,

R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;

R < ³ > is hydrogen or halogen;

R ^a is hydrogen or alkyl;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;

Each Y is independently CH or N;

t is 1 or 2;

z is 1 or 2.

In a further embodiment, the compounds of the invention are preferably of the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof:

here,

이고, A is

ego,

이고, L ₁ is

ego,

이고, B is

ego,

here,

R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;

R < ³ > is hydrogen or halogen;

R ^a is hydrogen or alkyl;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;

Each Y is independently CH or N;

t is 1 or 2;

Combinations of any of the above embodiments are also contemplated herein.

Preferred compounds are summarized in Table 6.

The compounds of the present invention can be synthesized by one of the general methods shown in Schemes 1-20. These methods are provided for illustrative purposes only and are not limited thereto.

General synthetic schemes for the preparation of 6-amino- or 6-bromo-7-azaindole building blocks are shown below.

Scheme 1

Commercially available 7-azaindole or approximately substituted 7-azaindole derivatives were treated with meta-chloroperbenzoic acid in a suitable solvent to obtain the corresponding N-oxide / meta-chlorobenzoic acid salts. Treatment of N-oxide / salt with dimethylsulfate in a suitable solvent, followed by reaction of ammonia with intermediates in a suitable solvent, afforded the desired 6-amino 7-azaindole building block.

The N-oxide salt was treated with base in a suitable solvent and N-oxide was obtained after purification. Reaction of hexamethyldisilazane and benzoylbromide with N-oxide in a suitable solvent afforded the corresponding N ¹ -benzoyl protected 6-bromo 7-azaindole derivative. The protecting group was saponified with sodium hydroxide in a suitable solvent and after purification the corresponding 6-bromo 7-azaindole derivatives were obtained. Protection of the N ¹ -position with the triisopropylsilyl moiety yielded the desired N ¹ -protected 6-bromo 7-azaindole derivative after purification.

General synthetic scheme for the preparation of 3-substituted 6-bromo 4-azaindoles and 6-bromo indole building blocks with R = Boc, CH ₃ and X = CH, N.

Scheme 2

Commercially available 6-bromo 4-indole (X = CH) was treated with sodium hydride in a suitable solvent followed by addition of triisopropylsilyl chloride to obtain N ¹ -protected derivatives after purification.

Commercially available 6-bromo 4-indole (X = CH) or 6-bromo 4-azaindole (X = N) was added to N-Boc-piperidin-4-one or N-methyl- in a suitable solvent. Treatment with piperidin-4-one and the appropriate base gave the condensation product after purification. The corresponding reduction product was obtained after hydrogenation and purification of the double bond using the appropriate catalyst and solvent. Protection of the N ¹ -position with the triisopropylsilyl moiety yielded the desired 3-substituted and N ¹ -protected derivatives after purification.

General synthetic scheme for the preparation of 3-substituted 5-bromo 7-azaindole and 5-bromo 7-indole building blocks with R = Boc, CH ₃ .

Scheme  3

Commercially available 5-bromo indole (X = CH) or 5-bromo 7-azaindole (X = N) was either N-Boc-piperidin-4-one or N-methyl-piperi in a suitable solvent. Condensation product was obtained after treatment with din-4-one and the appropriate base and purification. Protection of the N ¹ -position with the triisopropylsilyl moiety yielded the desired N ¹ -protected derivative after purification.

General synthetic scheme for the preparation of 3-substituted 6-amino indole building blocks of the invention with R = Boc, CH ₃ .

Scheme  4

Commercially available 6-nitro indole was treated with N-Boc-piperidin-4-one or N-methyl-piperidin-4-one and the appropriate base in a suitable solvent to give a condensation product after purification. The desired 6-amino indole derivatives were obtained after purification by reduction of the double bonds and nitro-groups using the appropriate catalyst and solvent. The protection of the N ¹ -position of the nitro derivative from the initial condensation with the triisopropylsilyl moiety yielded the corresponding compound which was used for hydrogenation without purification. The desired N ¹ -TIPS protected 6-amino indole derivatives were obtained after purification by reduction of the double bonds and nitro-groups using the appropriate catalyst and solvent. The protection of the N ¹ -position of the nitro derivative from the initial condensation containing the N-Boc protected piperidine moiety with methyl group gave the desired compound after purification. Catalytic reduction of the double bonds and nitro groups with an appropriate catalyst and solvent yielded the desired N ¹ -methyl protected 6-amino indole derivatives after purification, wherein the nitrogen of the piperidine moiety is protected with a Boc-moiety. .

R ¹ And preparation of tricyclic 2-bromo or 2-amino tetrahydro-pyrido [2,3- b ] indole building blocks when R ² combines to form a 5- or 6-membered ring containing carbon atoms General synthetic schemes for

Scheme  5

Commercially available 2,6-dibromo pyridine was treated with hydrazine hydrate in a suitable solvent to obtain mono hydrazine derivatives. Condensation with an appropriate cyclic ketone in an appropriate solvent afforded the desired hydrazone compound. Tricyclized cyclized product was obtained after purification by thermal Fischer-indole synthesis. Modification of the copper (I) -oxide mediated bromo derivative with ammonia yielded the desired tricyclic 2-amino pyrido [2,3- b ] indole derivative after purification.

R ¹ And R ² combines to form a 6-membered ring containing carbon atoms, which ring when substituted with NCH ₃ Boc is tricyclic 2-bromo tetrahydro-pyrido [2,3- b] indole (X = N, Y = Br, Z = H) or 6-bromo tetrahydro-carbazole (X = CH, Y = H, Z = Br) or 7-bromo tetrahydro-carbazole ( X = CH, Y = Br, Z = H) General synthetic scheme for the preparation of building blocks.

General synthetic schemes for the preparation of protected 4-amino- and 4-hydroxycyclohexanone derivatives and unprotected 4-hydroxycyclohexanone derivatives.

Scheme  6

The commercially available 4-amino-cyclohexanol hydrogen chloride salt was converted to the corresponding phthalimide-protected 4-amino-cyclohexanol using phthalimide reagent and potassium carbonate in a suitable solvent. Pyridinium chlorochromate was used in the appropriate solvent to oxidize the alcohol to a ketone and to purify to yield phthalimide-protected 4-amino-cyclohexanone. Commercially available 1,4-cyclohexanedione monoethylene acetal was treated with sodium borohydride in a suitable solvent to afford the corresponding alcohol. Treatment of alcohol with phthalimide using Mitsunobu reaction conditions yielded the desired compound after purification. The decomposition of acetal was carried out by refluxing the starting material with a small amount of p-toluene sulfonic acid in a suitable solvent mixture to give the corresponding phthalimide-protected 4-amino-cyclohexanone. Treatment of the alcohol reduction product with benzoyl chloride followed by decomposition of acetal with a small amount of p-toluene sulfonic acid with reflux in an appropriate solvent mixture afforded the corresponding benzoyl-protected 4-hydroxy-cyclohexanone. Treatment of the alcohol reduction product with a small amount of p-toluene sulfonic acid while refluxing in a suitable solvent mixture afforded the corresponding 4-hydroxy-cyclohexanone.

R ¹ And R ² combines to form a 6-membered ring containing carbon atoms, which ring when substituted with NR ²⁰ Boc is tricyclic 2-bromo tetrahydro-pyrido [2,3- b] indole (X = N, Y = Br, Z = H) or 3-bromo tetrahydro-pyrido [2,3-b] indole (X = N, Y = H, Z = Br) or 6- General for the preparation of bromo tetrahydro-carbazole (X = CH, Y = H, Z = Br) or 7-bromo tetrahydro-carbazole (X = CH, Y = Br, Z = H) building blocks Synthetic scheme

Scheme  7

2-bromo-6-hydrazino pyridine (X = N, Y = Br, Z = H) or 3-bromo-6-hydra with phthalimide protected 4-amino-cyclohexanone derivative in a suitable solvent Zino pyridine (X = N, Y = H, Z = Br) or 4-bromo-phenylhydrazine (X = CH, Y = H, Z = Br) or 3-bromo-phenylhydrazine (X = CH, Y = Br, Z = H) to give the desired hydrazone condensation product. Thermal Fischer-indole synthesis of hydrazone gave tricyclic cyclization product after purification. The phthalimide protecting group was removed by treatment with hydrazine hydrate in a suitable solvent to obtain a primary amine. The free amine was treated with the appropriate base and Boc-anhydride in the appropriate solvent to give mono-Boc and bis-Boc protected derivatives after purification. The mono-Boc derivative was treated with sodium hydride in a suitable solvent followed by methyl iodine to give the desired di-methyl tricyclic derivative after purification. The bis-Boc-protected compound was treated with sodium hydride in a suitable solvent, followed by addition of the appropriate alkylating agent to give a mono-alkylated product of X = CH after purification. Depending on the reactivity of the alkylating agent, the reaction proceeds at room temperature or requires elevated temperatures. By addition of the appropriate base in a suitable solvent, selective degradation of the Boc protecting group attached to the pyrrole ring of X = N is achieved to give the desired compound. The triisopropylsilyl moiety protects the NH-moiety of the pyrrole ring to give the desired tricyclic derivative of X = N after purification.

R ¹ And R ² combines to form a 6-membered ring containing carbon atoms, which ring when substituted with NR ²⁰ Boc is tricyclic 2-bromo tetrahydro-pyrido [2,3- b] indole (X = N, Y = Br, Z = H) or 3-bromo tetrahydro-pyrido [2,3-b] indole (X = N, Y = H, Z = Br) building blocks General Synthetic Schemes for Manufacturing

Scheme  8

Commercially available 2,6-di-bromo pyridine (X = N, Y = Br, Z = H) or 2,5-di-bromo pyridine (X = N, Y in a suitable solvent with suitable hydrazine derivatives = H, Z = Br) were heated to give the corresponding 2-bromo-6-hydrazino pyridine or 3-bromo-6-hydrazino pyridine derivative after purification. Condensation of the tricyclic cyclization products by condensation of commercially available 4- (methylamino) cyclohexanone 2,2-dimethyltrimethylene ketal hydrochloride and hydrazine derivatives in an appropriate solvent under acidic conditions used for Fischer-indole synthesis Got it. Treatment with the base gave the corresponding tricyclic cyclized product as the free base. The free amine was treated with Boc-anhydride and appropriate base in a suitable solvent to give a mono-Boc protected derivative after purification.

R ¹ And R ² combines to form a 6-membered ring containing carbon atoms, which ring of 6-membered tricyclic 2-bromo-6, when substituted at the same position with —CH ₃ and NR ²⁰ Boc; General synthetic scheme for the preparation of 9-dimethyl-tetrahydro-pyrido [2,3-b] indole (X = N, Y = Br, Z = H)

Scheme  9

Commercially available 4-hydroxycyclohexane carboxylic acid ethyl ester was treated with triisopropylsilyl-chloride in the appropriate solvent with the appropriate base to obtain a silyl-protected compound. Saponification of the base and the ester moiety in the appropriate solvent yielded the corresponding carboxylic acid. Treatment of carboxylic acid with excess lithium diisopropylamine, prepared in situ by the action of n-butyllithium on diisopropylamine, gives anion, which is quenched by the addition of methyl iodine, followed by C- 1 methylated carboxylic acid was obtained. The carboxylic acid is then converted to the protected amine via the Curtis-replacement reaction. In a suitable solvent, treatment of the isocyanate intermediate of Curtius displacement with the appropriate nucleophile, ie potassium tert -butylate, afforded the desired protected amine after purification. Treatment of amines protected with tetrabutyl ammonium fluoride in a suitable solvent afforded the desired 4-hydroxyl derivative after purification. Oxidation of the hydroxyl moiety with pyridinium chlorochromate in a suitable solvent afforded the corresponding cyclohexanone derivative after purification. Condensation of the appropriate hydrazine derivative with the ketone afforded the hydrazone compound. The hydrazone compound was then treated in a suitable solvent under the conditions of thermal Fischer-indole synthesis to obtain a cyclized product, which was treated directly with di- tert - butyl dicarbonate in a suitable solvent. This reaction gave a mixture of mono- and bis-Boc-protected products separated by chromatography. Bis-Boc derivatives were converted to mono-Boc derivatives by treatment with base in a suitable solvent. Treatment of the mono-Boc derivative with sodium hydride in a suitable solvent afforded the corresponding sodium salt which was then treated with an alkylating agent to give the desired product after purification. Depending on the reactivity of the alkylating agent, the reaction proceeds at room temperature or requires elevated temperatures.

R ¹ And R ² combine to form a 6-membered ring containing a carbon atom, which ring when substituted with OR ²⁰ is tricyclic 2-bromo tetrahydro-pyrido [2,3-b ] Indole (X = N, Y = Br, Z = H) or 3-bromo tetrahydro-pyrido [2,3-b] indole (X = N, Y = H, Z = Br) or 6-bro General synthesis for the preparation of parent tetrahydro-carbazole (X = CH, Y = H, Z = Br) or 7-bromo tetrahydro-carbazole (X = CH, Y = Br, Z = H) building blocks Scheme.

Scheme 10

The benzoyl protected 4-hydroxycyclohexanone was treated with the appropriate hydrazine-derivative in a suitable solvent to give a condensation product. The hydrazone-derivatives were treated using microwave under thermal Fischer-indole synthesis conditions to give tricyclic cyclized product after purification. Treatment of the tricyclic product with sodium hydride in a suitable solvent was followed by methyl iodine and the desired product was obtained after purification. Decomposition of the ester protecting group was carried out by heating with a base in an appropriate solvent using microwaves to afford the desired hydroxyl compound. After activation of the hydroxyl groups to their sodium salts using sodium hydride, alkylation of the hydroxyl groups with the appropriate alkylating agent is carried out in a suitable solvent. Depending on the reactivity of the alkylating agent, the reaction proceeds at room temperature or requires elevated temperatures. After purification, the desired product was obtained.

R ¹ And R ² combine to form a 6-membered ring containing carbon atoms, which ring when substituted with OCH ₃ is tricyclic 2-bromo tetrahydro-pyrido [2,3-b ] Indole (X = N, Y = Br, Z = H) or 3-bromo tetrahydro-pyrido [2,3-b] indole (X = N, Y = H, Z = Br) or 6-bro General synthesis for the preparation of parent tetrahydro-carbazole (X = CH, Y = H, Z = Br) or 7-bromo tetrahydro-carbazole (X = CH, Y = Br, Z = H) building blocks Scheme

Scheme  11

Unprotected 4-hydroxycyclohexanone was treated with the appropriate methyl-hydrazine-derivative in a suitable solvent to give a condensation product. Methyl-hydrazone-derivatives were treated using microwave under thermal Fischer-indole synthesis conditions to give tricyclic cyclized products after purification. Treatment of the tricyclic product with sodium hydride in a suitable solvent was followed by methyl iodine and the desired product was obtained after purification.

General Synthetic Schemes for the Preparation of Compounds of the Invention.

Scheme  12

By utilizing the Pd-coupling chemistry with the appropriate Pd-catalyst and the appropriate ligand in the appropriate solvent (X = CH, Y = N, Z = N, W = CH ₃ or TIPS) or (X = N, Y = CH, Z = CH, W = CH ₃ or TIPS) or (X, Z = CH, Y = N, W = CH ₃ or TIPS) or N- with (X, Y, Z = CH, W = CH ₃ or Boc) Protected bromo building blocks are either amine or (X, Y = CH, s = 0) or (X = N, Y = CH, s = 0) or (X = CH, Y = N, s = 0, It was reacted with an amine building block having 1, 2) to obtain the desired amination product after purification. Deprotection of the N-TIPS protected compound with tetra-n-butyl ammonium fluoride in a suitable solvent afforded the desired compound after purification. Treatment of the N-unprotected compound with hydrogen chloride in an appropriate solvent gave the final compound. Compounds with W = CH ₃ or Boc were treated with hydrogen chloride in a suitable solvent to give the final compound.

General Synthetic Schemes for the Preparation of Compounds of the Invention.

Scheme  13

N-protected bro and amine building blocks with the appropriate amine or (X, Z = CH) or (X = N, Z = CH) utilizing Pd-coupling chemistry with the appropriate Pd-catalyst and the appropriate ligand in the appropriate solvent The parent building block (Y = CH, W = CH ₃ , TIPS or Boc or Y = N, W = CH ₃ or TIPS) was reacted to give the desired amination product after purification. Deprotection of the N-TIPS protected compound with tetra-n-butyl ammonium fluoride in a suitable solvent afforded the desired compound after purification. Treatment of the N-unprotected compound with hydrogen chloride in an appropriate solvent gave the final compound. Compounds with W = CH ₃ or Boc were treated with hydrogen chloride in a suitable solvent to give the final compound.

General Synthetic Schemes for the Preparation of Compounds of the Invention.

Scheme  14

(Z = CH, W = H or CH ₃ or TIPS) or (Z = N, W = H or CH ₃ by utilizing the Pd-coupling chemistry with the appropriate Pd-catalyst and the appropriate ligand in the appropriate solvent Or TIPS) and (X = CH, Y = N, W = CH ₃ or TIPS) or (X = N, Y = CH, W = CH ₃ or TIPS) or (X, Y = N-protected bromo building blocks with CH, W = CH ₃ or TIPS) were reacted to give the desired amination product after purification. Deprotection of the N-TIPS protected compound with tetra-n-butyl ammonium fluoride in a suitable solvent afforded the desired compound after purification. Treatment of the N-unprotected compound with hydrogen chloride in an appropriate solvent gave the final compound. Compounds with (W = H or CH ₃ ) were treated with hydrogen chloride in a suitable solvent to afford the final compound.

General Synthetic Schemes for the Preparation of Compounds of the Invention.

Scheme 15

(Z = CH, W = H or CH ₃ or TIPS) or (Z = N, W = H or CH ₃ by utilizing the Pd-coupling chemistry with the appropriate Pd-catalyst and the appropriate ligand in the appropriate solvent Or reacting an appropriate amine building block with TIPS) with an N-protected bromo building block with (X = CH, W = CH ₃ or TIPS) or (X = N, W = CH ₃ or TIPS), After purification, the desired amination product was obtained. Deprotection of the N-TIPS protected compound with tetra-n-butyl ammonium fluoride in a suitable solvent afforded the desired compound after purification. Treatment of the N-unprotected compound with hydrogen chloride in an appropriate solvent gave the final compound. Compounds with (W = H or CH ₃ ) were treated with hydrogen chloride in a suitable solvent to afford the final compound.

R ¹ And a general scheme for the preparation of 2-bromo-tetrahydro-pyrido [2,3-b] indole building blocks when R ² combines to form a ring of (n + 4) -member containing carbon atoms

Scheme  16

Commercially available 2,6-dibromo pyridine in an appropriate solvent was treated with a hydrazine derivative (R = H, CH ₃ ) to give a mono hydrazine derivative. Condensation with an appropriate cyclic ketone in an appropriate solvent gave the desired hydrazone compound. Thermal Fischer-indole synthesis gave tricyclic cyclization product after purification.

R ¹ And tricyclic 7-bromo tetrahydro-pyrido [4,3-b] indole (X = Br) when R ² combines to form a ring of (n + 4) -member containing a carbon atom and NR ²⁰ , Y = H) or a general synthetic scheme for the preparation of 8-bromo tetrahydro-pyrido [4,3-b] indole (X = H, Y = Br) building blocks.

Scheme  17

Commercially available phenylhydrazine derivatives in appropriate solvents were treated with appropriate cyclic ketones to afford the desired hydrazone compounds. Fischer-indole synthesis gave the tricyclic cyclization product after purification. Treatment of the tricyclic derivatives with sodium hydride in a suitable solvent followed by treatment with the appropriate halogenated alkyl yielded the corresponding N-alkylated products. Subsequent deprotection of the carbamate derivative was carried out by adding sodium hydroxide in a suitable solvent under reflux conditions to give the desired compound. Finally, the aliphatic NH derivative was treated with sodium hydride in a suitable solvent and then derivatized by addition of appropriate halogenated alkyl to give the desired tricyclic derivative.

R ¹ And tricyclic 2-bromo-tetrahydro-pyrrolo [2,3-b: 4,5- when R ² combines to form a ring of (n + 4) -member containing a carbon atom and NR ²⁰ ; c '] dipyridine (X = N, Y = H, Z = Br), 3-bromo-tetrahydro-pyrrolo [2,3-b: 4,5-c'] dipyridine (X = N, Y = Br, Z = H), 7-bromo tetrahydro-pyrido [4,3-b] indole (X = CH, Y = H, Z = Br) or 8-bromo tetrahydro-pyrido [ 4,3-b] General synthetic scheme for the preparation of indole (X = CH, Y = Br, Z = H) building blocks.

Scheme  18

Commercially available hydrazine derivatives were treated with the appropriate cyclic ketones in the presence of the appropriate acid in the appropriate solvent to obtain the desired compound after purification via acidic Fischer-indole synthesis.

R ¹ And tricyclic 2-bromo-tetrahydrothiopyrano [3 ', 4': 4,5] when R ² combines to form a ring of (n + 4) -member containing carbon atoms and SO ₂ ; -Pyrrolo [2,3-b] pyridine-6,6-dioxide (X = Br, Y = H) or 3-bromo-tetrahydrothiopyrano [3 ', 4': 4,5] -py General Synthesis Scheme for Preparation of Rolo [2,3-b] pyridine-6,6-dioxide (X = H, Y = Br) Building Blocks.

Scheme  19

Commercially available phenylhydrazine derivatives in appropriate solvents were treated with appropriate cyclic ketones to afford the desired hydrazone compounds. Fischer-indole synthesis gave the tricyclic cyclization product after purification. Treatment of the tricyclic derivative with sodium hydride in a suitable solvent followed by treatment with the appropriate halogenated alkyl gave the corresponding N-alkylated product. Subsequent oxidation of the sulfur derivative with the appropriate oxidant gave the desired sulfone compound.

General synthetic schemes for the preparation of halogenated alkyl sulfones.

Scheme  20

The commercially available methylthioalcohol derivative was treated with a suitable oxidant in a suitable solvent to afford the desired hydroxysulfone derivative. Apel alcohol conditions were used to convert the monohydric alcohol compounds to the corresponding halogen derivatives in a suitable solvent.

All reagents and solvents were obtained from commercially available and used without further purification. Proton ( ¹ H) spectra were recorded on a Bruker EPX 400 MHz NMR spectrometer in deuterated solvent. Mass spectra (MS) were recorded on a Finnigan MAT TSQ 7000 spectrometer. Flash purification was performed with the Biotage Isolera One flash purification system using solvent gradients and HP-Sil SNAP cartridges (Biotage) shown in certain examples. Thin layer chromatography (TLC) was performed on silica gel plates with UV protection. Preparative thin layer chromatography (Prep-TLC) was performed with solvents and 0.5 mm or 1 mm silica gel plates (Analtech: Uniplate, F ₂₅₄ ) shown in the specific examples.

It is also possible for a compound of the invention to be administered alone, but it is preferred to formulate it into a pharmaceutical composition according to standard pharmaceutical practice. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in admixture with a pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 15 ^th Ed., Mack Publishing Co., New Jersey (1991). The pharmaceutical excipient may be selected in view of the standard pharmaceutical practice and the intended route of administration. The excipient should be acceptable from the point of view of the detainee.

Pharmaceutically useful excipients that can be used in the formulation of the pharmaceutical compositions of the invention include, for example, carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible fats, such as Soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, oily ester, such as ethyl oleate, isopropyl myristate, binder, adjuvant, solubilizer, thickener, stabilizer, disintegrant (disintegrant), glidant , Lubricants, buffers, emulsifiers, wetting agents, suspending agents, sweeteners, coloring agents, flavorings, coatings, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, Magnesium state, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dex Ross, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting wax, and ion exchange resins.

Routes for administration (delivery) of a compound of the invention include, but are not limited to: oral (e.g., as a tablet, capsule, or ingestible solution), topical, mucosal Intraperitoneal, intramuscular, intravenous, intrauterine, intravenous, intraperitoneal, intracranial, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, And include one or more of the following: intracerebral, intracerebroventricular, intracerebral, subcutaneous, intraocular (including intravitreal or anterior), transdermal, rectal, ball mucosa, epidural and sublingual.

For example, the compounds may be taken orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may be, for example, immediate-, delayed-, modified-, sustained-release, pulsed. Or flavoring or coloring agents for controlled-release applications.

The tablet may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate (glycollate), croscarmellose sodium and some complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, Gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be introduced. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar, or high molecular weight polyethylene glycols. As aqueous suspensions and / or elixirs, the formulations are combined with various sweetening or flavoring agents, coloring substances or dyes, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof Can be.

When the compound of the present invention is administered parenterally, examples of such administration include intravenous, intraarterial, intraperitoneal, intrathecal, intravenous, intraurethral, intradermal, intracranial, intramuscular or subcutaneous administration of the compound One or more of; And / or using an infusion technique. For parenteral administration, the compounds are best used in the form of sterile aqueous solutions which may contain other substances, for example, enough salts to make isotonic solutions with blood or glucose. The aqueous solution should be suitably buffered (preferably at a pH of 3 to 9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

As shown, the compounds of the present invention may be administered intranasally or by inhalation and include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, hydrofluoroalkanes such as 1, With the use of suitable propellants such as 1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas Is normally delivered in the form of a nebulizer or spray, a pump, an aerosol spray delivery from a pressurized container, or a dry powder inhaler. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Pressurized vessels, pumps, sprays or nebulizers may comprise a solution or suspension of the active compound, for example using a mixture of propellant and ethanol as solvent, which further comprises a lubricant, for example sorbitan trioleate (sorbitan trioleate). Cartridges and capsules (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to include a powder mix of the compound and a suitable powder base, such as lactose or starch.

Alternatively, the compounds of the present invention may be administered in the form of suppositories or pessaries, or topically in the form of gels, hydrogels, lotions, solutions, creams, ointments or dusting powders . The compounds of the present invention may also be administered dermally or transdermally, for example, by the use of a skin patch.

They may also be administered by the pulmonary or rectal route. They may also be administered by the ocular route. For ophthalmic use, the compounds are suspensions micronized in isotonic, pH adjusted, sterile saline, optionally in combination with preservatives such as benzalkonium chloride, preferably isotonic, pH adjusted, sterile saline. Can be formulated as a solution. Alternatively, they may be formulated into ointments such as petrolatum.

They may also be administered by the pulmonary or rectal route. They may also be administered by the ocular route. For ophthalmic use, the compounds are suspensions micronized in isotonic, pH adjusted, sterile saline, optionally in combination with preservatives such as benzalkonium chloride, preferably isotonic, pH adjusted, sterile saline. Can be formulated as a solution. Alternatively, they may be formulated into ointments such as petrolatum.

For topical application to the skin, the compounds of the present invention are suspended or dissolved in a mixture with one or more of: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water: It may be formulated in a suitable ointment containing the active compound. Alternatively they are for example mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water: It may be formulated as a suitable lotion or cream suspended or dissolved in a mixture with one or more.

Typically, the physician will determine the actual daily dose to be optimal for the individual subject. The frequency and specific dosage level of the dosage for an individual subject may vary and may vary depending upon the activity of the particular compound employed, the length and metabolic stability of the compound's activity, age, weight, general health, sex, The time and mode of administration, the rate of excretion, the drug combination, the severity of the particular condition, and the subject performing the treatment.

Preferred dosages of the compounds according to the invention for administration to humans (of about 70 kg body weight) are 0.1 mg to 1 g, preferably 1 mg to 500 mg of active ingredient per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it is necessary to perform routine variations on the dosage, which depend on the age and weight of the patient, as well as on the severity of the condition being treated. The exact dosage and route of administration will ultimately be at the discretion of the attending physician or veterinarian.

The compounds of the present invention may also be used in combination with other therapeutic agents. When a compound of the present invention is used in combination with a second therapeutic agent for the same disease, the dosage of each compound will differ from that when these compounds are used alone.

Combinations such as the above can be suitably presented for use in the form of pharmaceutical formulations. The individual components of such combination may be administered sequentially or simultaneously into a pharmaceutical formulation separated or combined by any convenient route. When the administration is sequential, either the compound of the present invention or the second therapeutic agent may be administered first. Where administration is simultaneous, the combination may be administered in the same or a different pharmaceutical composition. When combined in the same formulation, it will be understood that both compounds should be stable, compatible with each other and with other components of the formulation. If formulated separately, they can be conveniently provided in any convenient formulation in the same manner as is known for such compounds in the art.

The pharmaceutical compositions of the present invention may be prepared in a manner known to those skilled in the art, for example, as described in Remington's Pharmaceutical Sciences, 15 ^th Ed., Mack Publishing Co., New Jersey (1991).

Diseases that can be treated with the compounds of the present invention may be associated with the formation of abnormal protein structures, particularly abnormal < RTI ID = 0.0 > ss-sheet < / RTI > In the context of the present invention, an abnormal protein structure is a protein structure that occurs when a protein or peptide is folded back into a different three-dimensional structure associated with a pathological condition, from a three-dimensional structure generally associated with a healthy individual. Similarly, abnormal β-sheet structures in the context of the present invention are β-sheet structures that occur when a protein or peptide is folded back into a different β-sheet structure associated with a pathological condition, generally from a three-dimensional structure associated with a healthy individual. to be.

In particular, in one embodiment, the disease that may be treated with a compound of the invention is a disease or condition associated with an amyloid or amyloid-like protein.

Groups of these diseases and disorders include Alzheimer's disease (AD), diseases or conditions characterized by a loss of cognitive memory, such as, for example, mild cognitive impairment (MCI), Lewy body dementia, Down's syndrome ( Down's syndrome), amyloid hereditary cerebral hemorrhage with amyloidosis (Dutch type); Guam Parkinson-Dementia complex. Other diseases based on or associated with amyloid-like proteins include progressive supranuclear palsy, multiple sclerosis; Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, amyotropic lateral sclerosis (ALS), inclusion-body myositis (IBM), adult-onset diabetes (Adult) Onset Diabetes); Senile cardiac amyloidosis; Endocrine tumors, and different tissues of the eye, such as cortical visual defects; Optic nerve and anterior chambers, including glaucoma; A lens comprising cataracts due to beta-amyloid deposition; Vitreous, including amyloidosis; Primary retinal degeneration and macular degeneration, especially retinas including age-related macular degeneration; Optic nerve, including optic nerve drusen, optic neuropathy and optic neuritis; And other disorders involving amyloid-related eye diseases that target the cornea, including lattice dystrophy.

In a preferred embodiment, the compounds of the invention are used for Alzheimer's disease, mild cognitive impairment (MCI), Lewy body dementia (LBD), Amyotrophic sclerosis (ALS), inclusion body myositis (IBM) and age-related macular degeneration (AMD). It can be adopted for treatment. In particularly preferred embodiments, the compounds of the invention may be employed for the treatment of Alzheimer's disease.

The ability of a compound to inhibit the aggregation of A [beta] is described, for example, in Rzepecki et al., J. Biol. Can be measured using fluorescence correlation spectroscopy as described in Chem., 2004, 279 (46), 47497-47505, or using thioflavin T spectrofluorescence analysis.

In another embodiment, the compounds of the invention are related to pathological abnormalities / changes in tissues of the visual system, in particular ocular diseases associated with amyloid-beta-related pathological abnormalities / changes in tissues of the visual system, eg It can be used to treat or mitigate the effects of eye diseases such as neuronal degradation. Such pathological abnormalities include, for example, visual cortex resulting in cortical visual deficit; Optic nerve and anterior chamber that bring glaucoma; A lens that causes cataracts due to beta-amyloid deposition; A vitreous body that causes amyloidosis; Primary retinal degeneration and macular degeneration, such as retinas resulting in age-related macular degeneration; Optic nerve drusen, optic neuropathy that causes optic neuropathy and optic neuritis; And lattice dystrophy in the cornea of the eye.

The compounds according to the invention may also be provided in the form of a mixture, which comprises at least one additional biologically active compound and / or a pharmaceutically acceptable carrier and / or diluent and / or excipient. The compound and / or additional biologically active compound is preferably present in a therapeutically effective amount.

The nature of the additional biologically active compound will depend on the intended use of the mixture. Said additional biologically active substance or compound may exert its biological effect by a mechanism the same or similar to a compound according to the invention, or by an irrelevant mechanism of action, or by a combination of related and / or unrelated mechanism of action.

Generally, the additional biologically active compound is selected from the group consisting of a neutron-transmission enhancer, a psychotherapeutic drug, an acetylcholinesterase inhibitor, a calcium-channel blocker, a biogenic amine, a benzodiazepine- tranquillizer, acetylcholine synthesis, storage or release enhancer, acetylcholine synapse posterior receptor agonist, monoamine oxidase-A or -B inhibitor, N-methyl-D-aspartate glutamate receptor antagonist, nonsteroidal anti- , And serotonergic receptor antagonists. In particular, the additional biologically active compounds are useful as DNA repair inhibitors, such as compounds used in the treatment of amyloidosis, compounds against oxidative stress, anti-apoptotic compounds, chelator, pirenzepin and metabolites, (3APS), 1,3-propanedisulfonate (1,3PDS),? -Secretase activator,? - and? -Secretase inhibitors, tau A tau protein, a neurotransmitter, a beta-sheet breaker, an amyloid beta clearing / depleting attractant to cell components, pyroglutamated, Inhibitors of N-terminal truncated amyloid beta, including amyloid beta 3-42, anti-inflammatory molecules or tacrine, rivastigmine, donepezil, and / or galantamine, Such as choline esterase From inhibitors (ChEIs), M1 agonists, any amyloid or tau modified drug and other drugs, including nutritional supplements, antibodies comprising functionally equivalent antibodies or functional parts thereof, from the N-terminal portion of the Αβ peptide It can be selected from the group consisting of Αβ antigenic peptide fragments consisting of a single or repeated stretch of a plurality of consecutive amino acid residues.

In a further embodiment, the mixture according to the invention comprises niacin or a memantine and, optionally, a pharmaceutically acceptable carrier and / or diluent and / or excipient together with the compound according to the invention .

The mixture provided in another embodiment of the present invention may be used in combination with other agents such as hallucination, delusion, marked incoherence, derailment, tangentiality, for the treatment of positive and negative psychotic symptoms including anxiety, depression, anxiety, and disordered behavior, as well as anhedonia, flattened affect, apathy, and social withdrawal Quot; atypical antipsychotics ", which are additional biologically active compounds, such as, for example, clozapine, ziprasidone, risperidone, aripiprazole or olanzapine, Together with a compound according to the invention and, optionally, a pharmaceutically acceptable carrier and / or diluent and / or excipient.

Other compounds that may be suitably used in combination with the compounds according to the present invention include, but are not limited to, therapeutic drug targets (pages 36-39), alkanesulfonic acids and alkanol sulfates (pages 39-51), cholinesterase inhibitors (pages 51-56 ), NMDA receptor antagonists (pages 56-58), estrogens (pages 58-59), non-steroidal anti-inflammatory agents (pages 60-61), antioxidants (pages 61-62), peroxisome proliferator- Peroxisome proliferator-activated receptor (PPAR) agonists (pp. 63-67), cholesterol-lowering agents (pp. 68-75); Amyloid Inhibitors (pages 75-77), Amyloid Inhibitors (pages 77-78), Metal Chelaters (pages 78-79), Anti-Psychotropic and Anti-Depressants (pages 80-82), Nutritional Supplements (83-89) Page 2004) and WO 2004/058258 (especially 16), incorporated herein by reference, including prodrugs (pages 93 and 94) and compounds that increase the usefulness of biologically active substances in the brain (see pages 89-3). And page 17).

In one preferred embodiment, the additional biologically active compound is an antibody comprising any functionally equivalent antibody or functional site thereof. The antibody may preferably be monoclonal, chimeric or humanized.

In a further aspect of the invention there is provided a mixture comprising, in addition to a compound of the invention, an antibody comprising the functional site, more specifically a monoclonal antibody comprising the functional site, which comprises amyloid β (Aβ) , In particular, recognizes and binds to the natural conformational forms of amyloid β, ie amyloid oligomers and fibers, but not those that are not linearized amyloid species.

In particular, the antibodies can be used in vitro and in vivo to form amyloidogenic monomeric peptides, in particular β-amyloid monomeric peptides such as Aβ monomeric peptides 1-39; Aggregation of 1-40, 1-41, 1-42, or 1-43, among other things, Aβ _1-42 monomeric peptides into high molecular weight polymeric amyloid fibrils or filaments can be suppressed. Through the inhibition of the aggregation of amyloid-forming monomeric peptides, these antibodies become amyloid plaques, particularly amyloid-type (" amyloid ") forms which are known to be the most of amyloid plaques in diseased or human brains, Lt; RTI ID = 0.0 > 1-42). ≪ / RTI >

In another aspect of the invention, the mixture comprises amyloid monomeric peptides, in particular β-amyloid monomeric peptides such as Aβ monomeric peptides 1-39; Co-incubation with preformed high molecular weight polymeric amyloid fibrils or filaments, formed by aggregation of 1-40, 1-41, 1-42 or 1-43, especially among Aβ _1-42 monomeric peptides Bait (co-incubation) includes an antibody capable of dissociating the high molecular weight polymeric amyloid fibrils or filaments. Through disassembly of amyloidogenic polymeric fibrils or filaments, these antibodies can prevent or delay the formation of amyloid plaques, which alleviate the symptoms associated with the disease and delay or reversal its progression.

In another aspect of the invention, the mixture comprises an antibody, in particular a monoclonal antibody or a functional site thereof, wherein the antibody is disassembled as described above, with a particularly high degree of conformational sensitivity. It is bifunctional or bispecific in that it exhibits both properties as well as aggregation inhibitory properties.

In one embodiment, the mixture recognizes and binds to a conformational epitope, in particular a conformational epitope present in the N-terminal region of the amyloid β peptide, in particular in the following core region of the N-terminal region of the amyloid β peptide. Antibody.

In particular, the epitope is localized in the region of the β-amyloid protein between amino acid residues 12 to 24, in particular residues 14 to 23, more particularly between amino acid residues 14 to 20, the residues being primarily involved in the binding of β-amyloid protein, Three unique cognitive and binding sites located at positions 16, 17 and 19 and 20, and 14, respectively.

In certain embodiments, the mixtures of the present invention comprise, in addition to the compounds of the present invention, any functionally equivalent antibody or antibody comprising the functional site thereof, in particular bifunctional antibodies, in particular monoclonal antibodies, in particular bifunctional monoclonal antibodies Wherein the antibodies are DSM ACC2752, DSM ACC 2750 and DSM ACC2751, respectively, FP 12H3, FP 12H3-C2, and FP 12H3-G2, deposited on December 01, 2005 and December 09, 2005, respectively; Has the characteristic properties of an antibody prepared by a hybridoma cell line selected from the group consisting of ET 7E3 deposited on December 08, 2005 with DSM ACC2755, and EJ 7H3 deposited on December 08, 2005 with DSM ACC2756. .

More particularly, the present invention relates to DSM ACC2752, DSM ACC 2750 and DSM ACC2751, respectively, FP 12H3, FP 12H3-C2, and FP 12H3-G2 and DSM deposited on December 01, 2005 and December 09, 2005, respectively. Any functionally equivalent antibody prepared by a hybridoma cell line selected from the group consisting of ET 7E3 deposited on December 08, 2005 with ACC2755, and EJ 7H3 deposited on December 08, 2005 with DSM ACC2756, or It relates to an antibody comprising a functional site.

Such antibodies are described in published international application WO 2007/068412, which is incorporated herein by reference.

In a further aspect, the antibody comprised in the mixture according to the invention is a chimeric antibody or fragment thereof, or a humanized antibody or fragment thereof. These and additional antibodies that can be suitably used in the mixtures according to the invention are described, for example, in international application PCT / US2007 / 073504 (filed Jul. 13, 2007).

When the antibody is a humanized antibody, it preferably represents the light and heavy chains of SEQ ID NO: 2 and SEQ ID NO: 4 of International Application No. PCT / US2007 / 073504, or SEQ ID NO: 1 and of International Application No. PCT / US2007 / 073504 Light chain variable region and heavy chain variable region as set forth in SEQ ID NO: 3. These sequences are also shown in the attached base sequence.

In another aspect of the invention, in addition to the compounds according to the invention and as described above, peptide fragments from the N-terminal site of the Αβ peptide, in particular 13-15 consecutive amino acids from the N-terminal site of the Αβ peptide Αβ peptide fragments consisting of single or repeating stretches of residues, more particularly functionally equivalent fragments selected from the group consisting of residues 1-15, 1-14, and 1-13 from the N-terminal site of the Αβ peptide Aβ peptide fragment consisting of amino acid residues of residues 1-15, more particularly a mixture comprising the aforementioned Αβ peptide fragment attached, introduced or reconstituted to a carrier particle / adjuvant, such as, for example, a liposome. This is provided. The peptide fragment may be included in a vaccine composition. In particular, peptide antigens act as anchors to peptides, particularly in lipid bilayers, by lipophilic or hydrophobic moieties that facilitate the insertion of the liposome carrier / immunoadjuvant into the lipid bilayer, Lt; RTI ID = 0.0 > hydrophobic < / RTI >

In a further embodiment of the invention, the lipophilic or hydrophobic moiety is a fatty acid, triglyceride or phospholipid, especially fatty acids, triglycerides or phospholipids. In particular, the hydrophobic moiety is palmitic acid and the liposome preparation is also an adjuvant such as lipid A, alum, calcium phosphate, interleukin 1, and / or microcapsules of polysaccharides and proteins, particularly detoxified lipid A Such as monophosphoryl or diphosphoryl lipid A, or alum.

These and further compositions which can be suitably used in the mixtures of the invention are described, for example, in published international application WO 2007/068411.

Predisposition to amyloid-related diseases or conditions in a patient or diagnosis of amyloid-related diseases or conditions is a step of detecting specific binding of a compound according to the invention to amyloid protein in a sample or in situ , Contacting a sample or specific body part or body region suspected of containing an amyloid antigen with a compound according to the invention, wherein the compound of the invention is allowed to bind to the amyloid protein to form a compound / protein complex Detecting the formation of the compound / protein complex, correlating the presence or absence of the compound / protein complex with the presence or absence of amyloid protein in the sample or specific body part or body region, optionally, the compound Of protein complex Can be achieved by comparing the to a normal control value, wherein an increase in the amount of aggregates relative to the normal control value is at risk of progressing or the patient is suffering from an amyloid-related disease or condition. Can be represented.

Monitoring for minimal residual disease in a patient after treatment with a compound or mixture according to the invention is a step of detecting specific binding of the compound according to the invention to an amyloid protein in a sample or in situ , which contains an amyloid antigen. Contacting a sample or specific body part or body region suspected to be with a compound of the invention that binds to an amyloid protein, allowing the compound to bind to the amyloid protein to form a compound / protein complex, Detecting the formation of said compound / protein complex, and correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or particular body part or body region, optionally, said compound / Protein complex And the amount of can be achieved by comparing the value of the normal control group, in which the increase in the amount of the normal value than the control group agglomerates may indicate that the patient is receiving still suffer from minimal residual disease.

Predicting a patient's responsiveness to treatment with a compound or composition or mixture according to the invention is the step of detecting the specific binding of the compound according to the invention to an amyloid protein in a sample or in situ . Contacting a sample or specific body part or body region suspected of containing with a compound of the invention that binds to an amyloid protein, allowing the compound to bind to the amyloid protein to form a compound / protein complex Detecting the formation of said compound / protein complex, and correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region, optionally, Before and after Comparing the amount of the compound / protein complex, wherein a decrease in the amount of aggregates may indicate that the decrease in the amount of aggregates indicates that the patient has a high potential to respond to the treatment. have.

In a further aspect of the invention, the compound of formula (I) may contain radionuclides (eg, ¹²⁵ I, ¹²⁴ I, ¹²³ I or ¹⁸ F). These compounds may be useful for in vivo diagnosis or imaging of amyloid-related diseases, preferably Alzheimer's disease, for example in methods such as single photon emission tomography (SPECT imaging) or positron emission tomography (PET). have.

In radiopharmaceutical applications, the compounds of the invention are preferably administered in radiopharmaceutical formulations comprising the compounds of the invention. A "radiopharmaceutical formulation" is defined herein as a formulation comprising a compound of the invention (such as a compound of formula (I) or a salt thereof) in a form suitable for administration to a mammal, such as a human. Preferably the radiopharmaceutical formulation further comprises a physiologically acceptable excipient. Administration is preferably carried out by injection of the formulation as an aqueous solution. Such formulations may optionally include additional ingredients such as buffers; Pharmaceutically acceptable solubilizers (eg cyclodextrins or surfactants such as Pluronic, Tween or phospholipids); It may contain a pharmaceutically acceptable stabilizer or antioxidant (such as ascorbic acid, gentic acid or para-aminobenzoic acid). The dosage of the compound of the present invention will vary depending on the exact compound to be administered, the weight of the patient, and other variables as will be apparent to a physician skilled in the art. In general, the dosage ranges from 0.001 μg / kg to 10 μg / kg, preferably from 0.01 μg / kg to 1.0 μg / kg.

Amyloid for the determination of the susceptibility to amyloid-related diseases or conditions, or for monitoring the minimal residual disease in a patient, or for predicting the response of a patient as described above, and for treating with a compound or composition or mixture according to the invention A biological sample that can be used for the diagnosis of a related disease or condition is obtained from an organism such as, for example, serum, plasma, saliva, digestive discharge, fluid such as mucus, spinal fluid, lymph fluid or the like or nerve, brain, It is a tissue or cell sample. To determine the presence or absence of amyloid proteins in a sample, for example, routine assays in the art, such as assays using indirect detection methods using secondary reagents for detection, ELISA's and immunoprecipitation and agglutination assays. Any immunoassay known to the person skilled in the art (see Harlow and Lane, Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory, New York 1988 555-612)) can be used. A detailed description of these assays is provided, for example, in WO 96/13590, Zrein et al. (1998), and WO 96/29605 to Maertens and Stuyver.

For in situ diagnosis, the compounds or compositions or mixtures described above, and according to the present invention, may be used in methods known in the art such as, for example, intravenous, intranasal, intraperitoneal, intracranial, intraarterial injection. It can be administered to a living body to be diagnosed, whereby specific binding between the compound according to the invention and the amyloid antigen can occur. Compound / protein complexes can be detected via a label attached to the compound.

Diagnostic application, or diagnosis of predisposition to amyloid-related diseases or conditions, or responsiveness of a patient to monitoring minimal residual disease in a patient, or as described above, and to treatment with a compound, composition, or mixture according to the invention Immunoassays used in applications for predicting these are generally dependent on labeled antigens, antibodies, or secondary reagents for detection. These proteins or reagents may be labeled with compounds generally known to those skilled in the art, including enzymes, radioisotopes, and chromogenic materials including fluorescent particles, luminescent materials, and colored particles such as colloidal gold and latex beads. . Of these, radiolabels can be used for most all types of analyses and also with most variants. Enzyme-conjugated labels are particularly useful when radioactivity should be avoided or when fast results are needed. Fluorochromes provide a very sensitive detection method despite the expensive equipment required for their use. Antibodies useful for these assays include monoclonal antibodies, polyclonal antibodies, and affinity purified polyclonal antibodies.

Alternatively, the compounds of the present invention may be indirectly labeled by action with labeled substances having affinity for immunoglobulins or secondary antibodies such as protein A or G. The antibody may be conjugated with a secondary substance and detected as a labeled third substance having an affinity for the secondary substance conjugated to the antibody. For example, the antibody can be conjugated to biotin, and the antibody-biotin conjugate can be detected using labeled avidin or streptavidin. Similarly, the antibody can be conjugated to a hapten and the antibody-hapten conjugate can be detected using a labeled anti-hapten antibody.

Those skilled in the art will be familiar with these and other suitable labels that may be employed in accordance with the present invention. Binding of these labels to antibodies or fragments thereof can be accomplished using standard techniques generally known to those skilled in the art. General techniques have been described by Kennedy, J. H., et al., 1976 (Clin. Chim. Acta 70: 1-31), and Schurs, A. H. W. M., et al. 1977 (Clin. Chim Acta 81: 1-40). The coupling techniques mentioned in the latter are the glutaraldehyde method, the periodate method, the dimaleimide method, and others, all of which are incorporated herein by reference.

Current immunoassays use a dual antibody method to detect the presence of an analyte, where the antibody is indirectly labeled by reactivity with a secondary antibody labeled with a detectable label. The secondary antibody is preferably one that binds to the antibody of the animal from which the monoclonal antibody is derived. In other words, if the monoclonal antibody is a mouse antibody, the labeled secondary antibody is an anti-mouse antibody. For monoclonal antibodies used in the assays described below, this label is preferably antibody-coated beads, in particular magnetic beads. For polyclonal antibodies used in the immunoassays described herein, the label is preferably a detectable molecule, such as a radioactive, fluorescent or electrochemiluminescent material.

An alternative double antibody system, often referred to as a fast format system, can also be used within the scope of the present invention because it is flexible to rapid measurement of the presence of an analyte. The system requires high affinity between the antibody and the analyte. According to one embodiment of the invention, the presence of the amyloid antigen is measured using a pair of antibodies, each specific for the amyloid antigen. One of the pair of antibodies is referred to herein as a "detector antibody," and the other of the pair of antibodies is referred to herein as a "capture antibody." The monoclonal antibody can be used as either a capture antibody or a detector antibody. The monoclonal antibodies may be used together as both capture and detector antibodies in a single assay. Thus, one embodiment of the present invention uses the dual antibody sandwich method to detect amyloid antigen in a sample of biological fluid. In this method, the analyte (amyloid antigen) is sandwiched between a detector antibody and a capture antibody, and the capture antibody is irreversibly immobilized on a solid support. The detector antibody contains a detectable label to confirm the presence of the antibody-analyte sandwich to confirm the presence of the analyte.

Exemplary solid phase materials include, but are not limited to, microtiter plates known in the art of radioimmunoassay and enzyme immunoassay, test tubes of polystyrene, magnetic, plastic or glass beads and slides do. Methods for coupling antibodies to solid phases are also known to those skilled in the art. More recently, a number of porous materials such as nylon, nitrocellulose, cellulose acetate, glass fibers, and other porous polymers have been used as solid supports.

Ocular diseases associated with amyloid-beta-related pathological abnormalities / changes in tissues and / or body fluids (such as animals, in particular mammals, more particularly tissues of the visual system, in particular tissues of the visual system) Plaque load in the retinal ganglion cell layer of human suffering from, Ding, J. -D. Related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-b antibody attenuates pathologies in an age-related macular degeneration mouse model "(Vision Research (2007), doi: 10.1016 / j.visres.2007.07 .025). ≪ / RTI >

The compounds according to the invention may also be introduced into test kits for the detection of amyloid proteins. The test kit is typically bound to a container containing one or more compounds according to the present invention and an amyloid protein to form a compound / protein complex and to detect the formation of the compound / protein complex, thereby the presence or absence of the compound / protein complex. Instructions for use of the compound for the purpose of correlating each other with the presence or absence of the amyloid protein.

The term "test kit" generally refers to any diagnostic kit known in the art. More specifically, the latter term refers to a diagnostic kit as described in Zrein et al. (1998).

Inhibition of aggregation of Aβ _1-42 by the compounds of the present invention can be measured using any suitable assay known in the art. Standard in vitro assays for measuring inhibition of aggregation are described.

Synthesis of compounds of the invention that inhibit aggregation of Aβ _1-42 and their biological activity assays are described in the Examples below, which are not intended to be limiting in any way.

Example

All reagents and solvents were obtained from commercially available and used without further purification. Proton ( ¹ H) spectra were recorded on a 400 MHz NMR spectrometer in deuterated solvent. Mass spectra (MS) were recorded on a Finnigan MAT TSQ 7000 spectrometer. Chromatography was performed using the appropriate solvent and silica gel (Fluka: silica gel 60, 0.063-0.2 mm) shown in the specific examples.

Flash purification was performed with the Biotage Isolera One flash purification system using solvent gradients and HP-Sil SNAP cartridges (Biotage) shown in certain examples. Thin layer chromatography (TLC) was performed on silica gel plates with UV protection. Preparative thin layer chromatography (Prep-TLC) was performed with solvents and 0.5 mm or 1 mm silica gel plates (Analtech: Uniplate, F ₂₅₄ ) shown in the specific examples.

Production Example 1

Step A

Commercially available 7-azaindole (1.98 g, 16.8 mmol) was dissolved in a mixture of 1,2-dimethoxyethane and n-heptane (30 mL, 1: 2) and the mixture was placed in a cold water bath. M-chloroperoxybenzoic acid (5.1 g, 19.5. Mmol, ˜77%) was then added with partial stirring. A precipitate formed after half the m-chloroperoxybenzoic acid was added. After the addition was complete, the mixture was stirred at rt overnight. The precipitate was collected by filtration, washed with 1,2-dimethoxyethane / n-heptane (10 mL, 1: 2) and air dried to give the m-chloroperoxybenzoic acid salt of the title compound as a white solid (4.41). g, 91%). The salt was suspended in water (45 mL) and aqueous potassium carbonate solution was added until pH ˜9. The solvent was removed and the residue was purified by chromatography on silica using dichloromethane / methanol (9/1) as the mobile phase to give the title compound as an off-white solid (2 g, 91%).

Step B

The title compound (1 g, 7.46 mmol) from step A was dissolved in toluene (150 mL). To this solution was added dropwise a solution of hexamethyldisilazane (1.56 mL, 7.46 mmol) in toluene (75 mL) and a solution of benzoylbromide (2.24 mL, 18.64 mmol) in toluene (75 mL) simultaneously. After the simultaneous addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate (30 mL), brine (30 mL) and the organic phase was separated. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (10/90) to afford the title compound as a white solid (1.48 g, 65%), which was used directly in the next step.

Step C

The title compound (1.48 g, 4.9 mmol) from Step B above was dissolved in methanol (90 mL) and 1 M sodium hydroxide solution was added. The mixture was stirred at rt overnight and filtered to remove insoluble matter. The filtrate was evaporated and the residue suspended in dichloromethane (100 mL). The mixture was sonicated and then stirred for 30 minutes at room temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on silica using dichloromethane / methanol (9/1) as the mobile phase to give the title compound as a white solid (0.59 g, 60%).

Step D

The title compound (0.59 g, 2.99 mmol) from Step C above was dissolved in tetrahydrofuran (10 mL) and the solution was cooled to 0 ° C. Sodium hydride (0.08 g, 3.3 mmol) was partially added at 0 ° C. After the addition was complete the mixture was stirred at room temperature for 15 minutes. Triisopropylsilyl-chloride (0.4 mL, 3 mmol) was then added and the mixture was heated at ˜85 ° C. for 3 hours in a sand bath. The mixture was diluted with ethyl acetate (50 mL) and brine (15 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (10/90) to give the title compound as a colorless oil (0.53 g, 50%).

Step E

The title compound (0.045 g, 0.127 mmol) and commercially available 2- (2-aminoethyl) -pyridine (0.015 g, 0.127 mmol) from the above preparation step D were dissolved in toluene (2 mL), 2,2 Treated with -bis- (diphenylphosphino) -1,1-naphthalene (0.016 g, 0.025 mmol) and sodium tert-butylate (0.031 g, 0.33 mmol). The reaction mixture was then degassed by bubbling argon through the reaction mixture followed by addition of tris (dibenzylideneacetone) dipalladium chloroform complex (0.011 g, 0.0126 mmol). The reaction vessel was sealed and the mixture heated at ˜115 ° C. for 45 minutes in a sand-bath. The reaction mixture was diluted with ethyl acetate (20 mL), saturated sodium bicarbonate (5 mL) and brine (5 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (20/80) to elute less polar byproducts, and then purified by ethyl acetate / n-heptane (40/60) to give the title The compound was obtained as a pale orange oil (0.04 g, 80%).

Production Example 2

Step A

Preparation Example 1 The title compound (0.045 g, 0.127 mmol) from Step D and commercially available 2- (aminomethyl) -pyridine (0.015 g, 0.127 mmol) were dissolved in toluene (2 mL) and 2,2- Treated with bis- (diphenylphosphino) -1,1-naphthalene (0.016 g, 0.025 mmol) and sodium tert-butylate (0.031 g, 0.33 mmol). The reaction mixture was then degassed by bubbling argon through the reaction mixture followed by addition of tris (dibenzylideneacetone) dipalladium chloroform complex (0.011 g, 0.0126 mmol). The reaction vessel was sealed and the mixture heated at ˜115 ° C. for 45 minutes in a sand-bath. The reaction mixture was diluted with ethyl acetate (20 mL), saturated sodium bicarbonate (5 mL) and brine (5 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (20/80) to elute less polar byproducts, and then purified by ethyl acetate / n-heptane (40/60) to give the title The compound was obtained as a pale orange oil (0.044 g, 90%).

Production Example 3

Step A

To a commercially available 7-azaindole (5 g, 42.3 mmol) solution in diethyl ether (350 mL) m-chloro perbenzoic acid (11 g, 63.4 mmol) was added in part at room temperature. The reaction mixture was stirred at rt for 5 h. The precipitated product was filtered off and washed with diethyl ether (50 mL). The solid was collected and dissolved in a mixture of water / acetone (50 mL / 10 mL) with heating. The mixture was cooled to 5 ° C. and the crystallized product was filtered and air dried to give the title compound (11.7 g, 96%).

Step B

To a suspension of the title compound (2 g, 6.92 mmol) from Step A above in dry acetonitrile (15 mL) was added dimethylsulfate (0.885 g, 6.92 mmol). The reaction mixture was heated at 70 ° C. for 8 hours. The clear solution was then cooled to room temperature. The solution was partitioned into three sealed tubes and cooled to 0 ° C. under argon atmosphere. A solution of 7 M ammonia in methanol (5 mL) was then added to each tube. The sealed tube was heated at 50-60 ° C. for 48 hours. The solvent was removed and the residue was dissolved in ethyl acetate (200 mL) and the organic phase was washed with diluted Na ₂ CO ₃ solution, water, and brine. The organic phase was dried over Na ₂ SO ₄ . The solvent was evaporated and the crude product was purified by chromatography on silica using ethyl acetate to give the title compound (0.5 g, 54%).

Production Example 4

Step A

To a commercially available solution of 3-cyano-7-azaindole (2 g, 13.9 mmol) in tetrahydrofuran (150 mL) was added m-chloro perbenzoic acid. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and dried to give the title compound (1.89 g, 86%).

Step B

To the suspension of the title compound (1.89 g, 11.8 mmol) from Step A above in dry acetonitrile (15 mL) was added dimethylsulfate (1.5 g, 11.8 mmol) and the reaction mixture was heated at 80 ° C. overnight. The clear solution was cooled to room temperature and transferred to three 5 mL tubes. A solution of 7 M ammonia in methanol (5 mL) was then added to each tube. The sealed tube was heated at 70 ° C. for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethyl acetate and n-heptane to give the title compound (0.9 g, 48%).

Production Example 5

Step A

To a commercially available 6-bromoindole (0.5 g, 2.55 mmol) solution in tetrahydrofuran (20 mL) was added sodium hydride (0.095 g, 3.22 mmol) partially at room temperature. The suspension was stirred at rt for 10 min and triisopropylsilyl chloride (0.489 g, 2.55 mmol) was added slowly. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with water, brine and dried over Na ₂ SO ₄ . Removal of solvent under reduced pressure gave a residue, which was then purified by silica gel column chromatography (ethyl acetate / n-heptane 25/75) to give the title compound (0.890 g, 99%).

Production Example 6

Step A

To a commercially available 6-bromoindole (2.5 g, 12.7 mmol) solution in methanol (15 mL) was added a 25% sodium methoxide solution in methanol (2 mL) and the reaction mixture was heated at 80 ° C. for 2 days. . The reaction mixture was then concentrated to one third of its volume, poured into ice water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phase was washed with water, brine and dried over Na ₂ S0 ₄ . Removal of solvent under reduced pressure gave the crude product, which was then purified by column chromatography on silica (ethyl acetate / n-heptane (20/80)) to afford the title compound (3.5 g, 72%).

Step B

To a solution of the title compound (1.5 g, 3.97 mmol) from Step A in methanol (25 mL) was added triethyl amine (0.8 g, 7.94 mmol) and the mixture was degassed. Platinum (IV) -oxide (0.18 g, 0.79 mmol) was then added to the reaction mixture which was then evacuated and backfilled with hydrogen gas. The procedure was repeated 2-3 times and the reaction mixture was kept overnight under hydrogen atmosphere. The reaction mixture was then filtered off through a pad of celite. The filtrate was concentrated and dissolved in ethyl acetate (200 mL) and the organic phase was washed with water, brine and dried over Na ₂ SO ₄ . Removal of solvent under reduced pressure gave the crude product which was then purified on a column on silica to give the title compound (0.95 g, 63%).

Step C

To a solution of the title compound (0.7 g, 1.84 mmol) from Step B above in tetrahydrofuran (10 mL) was added sodium hydride (0.088 g, 3.68 mmol) and the suspension was stirred for 10 minutes. Triisopropylsilyl chloride (0.353 g, 1.84 mmol) was then added. The reaction mixture was stirred for 30 minutes. The reaction mixture was poured into ethyl acetate (200 mL), washed with water, brine and dried over Na ₂ SO ₄ . Removal of solvent under reduced pressure gave the crude product, which was then purified on silica gel column using ethyl acetate / n-heptane (5/95 to 50/50) to give the title compound (0.9 g, 91%).

Preparation Example 7

Step A

Methanol (4 mL) in a solution of commercially available 6-bromo-4-aza-indole (3 g, 15.3 mmol) and 1-Boc-4-piperidone (3.8 g, 19 mmol) in methanol (30 mL) , 18.5 mmol) in a 25% sodium methoxide solution. The reaction mixture was then stirred at 80 ° C. for 3 hours. At this time the reaction mixture was cooled to room temperature, poured into ice water (20 mL) and extracted with ethyl acetate (350 mL). The organic phase was washed with water, and brine solution. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the crude product which was then purified on silica gel column to give the title compound (3 g, 52%).

Step B

To a solution of the title compound (0.45 g, 1.19 mmol) from Step A in methanol (25 mL) was added triethyl amine (54 mg, 0.53 mmol) and the mixture was degassed. After platinum (IV) -oxide (0.062 g, 0.185 mmol) was added, the reaction mixture was evacuated and backfilled with hydrogen gas (repeats two more times). The reaction mixture was stirred for 16 h under hydrogen atmosphere. The reaction mixture was filtered off through celite and the filtrate was concentrated. The residue was then purified on silica gel column using ethyl acetate / n-heptane (10/90) to give the title compound (0.185 g, 42%).

Step C

To a solution of the title compound (0.110 g, 0.28 mmol) from Step B above in tetrahydrofuran (5 mL) was added sodium hydride (0.014 g, 0.56 mmol). The suspension was stirred at rt for 10 min. After triisopropylsilyl chloride (0.055 g, 0.28 mmol) was added, the reaction mixture was stirred at room temperature for 30 minutes. At this time, the reaction mixture was quenched with water, poured into ethyl acetate (150 mL) and washed with water and brine solution. The organic phase was separated, dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel column to give the title compound (0.105 g, 70%).

Production Example 8

Step A

To a solution of commercially available 5-bromo-7-azaindole (3 g, 15.2 mmol) and 1-Boc-4-piperidone (4.2 g, 21.1 mmol) in methanol (25 mL) methanol (4 mL, 18.5 mmol) in 25% sodium methoxide. The reaction mixture was then stirred at 80 ° C. for 2 days. The reaction mixture was poured into ethyl acetate (350 mL) and washed with water and brine solution. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the crude product, which was then crystallized from ethyl acetate / n-heptane mixture to give the title compound (4.2 g, 73%).

Step B

To a stirred solution of the title compound (3.2 g, 8.4 mmol) from Step A above in tetrahydrofuran was added sodium hydride (0.3 g, 12.6 mmol) and the suspension was stirred at room temperature for 10 minutes. Triisopropylsilyl chloride (1.62 g, 8.4 mmol) was then added slowly. The reaction mixture was stirred at room temperature for 2 hours. At this time, the reaction mixture was quenched with water and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with water and brine solution. The organic phase was dried over Na ₂ SO ₄ . Removal of solvent gave the crude product, which was purified on a silica gel column to give the title compound (3.3 g, 75%).

Step C

Triethylamine (0.6 g, 6.0 mmol) was added to a solution of the title compound (1.63 g, 3.0 mmol) from Step B above in methanol (20 mL). The mixture was degassed and platinum (IV) -oxide (0.14 g, 0.6 mmol) was added. The flask was then evacuated twice and backfilled with hydrogen gas. The reaction mixture was stirred for 16 h under hydrogen atmosphere. The heterogeneous reaction mixture was filtered off through celite. The filtrate was concentrated under reduced pressure to afford the crude product which was purified on a silica gel column to give the title compound (0.240 g, 50%).

Production Example 9

Step A

In a solution of commercially available 5-bromoindole (3.5 g, 17.9 mmol) in methanol (50 mL) in 1-Boc-4-piperidone (5.1 g, 25.6 mmol) and methanol (8 mL, 37 mmol) A solution of 25% sodium methoxide was added and the reaction mixture was heated at 80 ° C. for 2 days. The reaction mixture was filtered off. The solid was washed twice with ethyl acetate and dried under vacuum to afford the title compound (3 g). The filtrate was diluted with ethyl acetate (250 mL), washed with water, brine and dried over Na ₂ SO ₄ . Removal of solvent under reduced pressure gave the crude product, which was purified on a silica gel column to give additional title compound (2.9 g). The combined yield was 5.9 g, 86%.

Step B

To a degassed solution of the title compound (1.8 g, 4.7 mmol) from Step A above in ethyl acetate (50 mL) was added platinum (IV) -oxide (0.2 g, 0.88 mmol). The reaction mixture was evacuated and backfilled with hydrogen gas. The procedure was repeated twice and the reaction mixture was placed under hydrogen atmosphere overnight at room temperature. The reaction mixture was filtered off through celite and the filtrate was concentrated. The crude product was purified on silica gel column using ethyl acetate / n-heptane (10/90 to 50/50) to give the title compound (0.75 g, 42%).

Step C

To a solution of the title compound (0.6 g, 1.58 mmol) from Step B above in tetrahydrofuran (20 mL) was added sodium hydride (0.056 g, 2.37 mmol) and the suspension was stirred at rt for 10 min. Triisopropylsilyl chloride (0.34 g, 1.58 mmol) was then added and the mixture was stirred at rt for 1 h. The reaction mixture was quenched with water and concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with water and brine solution. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the crude product which was purified on silica gel column using ethyl acetate / n-heptane (10/90) to give the title compound (0.6 g, 70%).

Production Example 10

Step A

To a solution of the title compound (0.625 g, 1.64 mmol) from Preparation Example 9 step B in THF (10 ml) was added NaH (0.059 g, 2.4 mmol). The suspension was stirred for 5 minutes. Then methyliodine (0.346 g, 2.46 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the crude product was purified on silica gel column (20-50%; EtOAC vs. heptanes) to afford the title compound (0.485 g, 75%).

Production Example 11

To a solution of the title compound (500 mg, 0.1.31 mmol) in THF (10 ml) was added NaH (63 mg, 2.6 mmol) and the suspension was stirred for 5 minutes. Methyl iodine (185 mg, 0.131 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was then quenched with water and extracted with ethyl acetate (50ml x 3). The organic phase was washed with brine, dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was purified on silica gel column (EtOAc: heptane; 20:30) to give the title compound (485 mg, 94%).

Production Example 12

Step A

To a solution of 5-bromoindole (5 g, 25.3 mmol), and 1-methylpiperidin-4-one (4.3 g, 38.2 mmol) in methanol (50 mL) (28%) in methanol (10 mL) NaOMe was added and the reaction mixture was heated at 90 ° C. for 2 days. The product was precipitated, filtered off and dried under vacuum to give the title compound (6.3 g, 85%).

Step B

To a solution of the title compound (0.5 g, 1.72 mmol) from Step A above in THF (100 mL) was partially added sodium hydride (0.1 g, 4.28 mmol) and the suspension was stirred at rt for 10 min. Triisopropylsilyl chloride (0.33 g, 1.72 mmol) was then introduced slowly and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with water and the solvent was removed. The residue was dissolved in ethyl acetate (150 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . Solvent was removed and the residue was purified on silica gel column (methanol to EtOAc 10% to 20%) to give the title compound (0.498 g, 65%).

Step C

A solution of the title compound (0.490 g, 1.09 mmol) from Step B above in ethyl acetate (50 mL) was degassed and platinum (IV) -oxide (0.150 g, 0.67 mmol) was added. The reaction mixture was evacuated and backfilled with hydrogen gas. The procedure was repeated 2-3 times and the reaction mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered through a pad of acelite. The filtrate was concentrated and dissolved in ethyl acetate (200 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . Removal of solvent under reduced pressure afforded the crude product, which was then purified on silica gel column (MeOH to ethyl acetate 5% to 12%) to afford the title compound (0.15 g, 30%).

Production Example 13

Step A

To a solution of 1-methylpiperidin-4-one (3.4 g, 30.6 mmol) and 6-bromoindole (3 g, 15.3 mmol) in methanol (50 mL) NaOMe in methanol (10 mL) (28%) Was added and the reaction mixture was heated at 90 ° C. for 2 days. The precipitated product was filtered off and dried under vacuum to afford the title compound (4.1 g, 91%).

Step B

To a solution of the title compound (2 g, 6.8 mmol) from Step A above in THF / dioxane (100 mL / 10 mL) was partially added sodium hydride (0.25 g, 10.3 mmol) and the suspension was allowed to stand at room temperature for 10 minutes. Stirred. Triisopropylsilyl chloride (1.3 g, 6.8 mmol) was then introduced slowly and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with water, the solvent was removed and the residue was dissolved in ethyl acetate (200 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . The solvent was removed and the residue was purified on silica gel column (methanol to EtOAc 5% to 20%) to give the title compound (2.9 g, 95%).

Step C

A solution of the title compound (2.8 g, 6.2 mmol) from Step B above in ethyl acetate (50 mL) was degassed and platinum (IV) -oxide (0.18 g, 0.79 mmol) was added. The reaction mixture was then evacuated and backfilled with hydrogen gas. The procedure was repeated 2-3 times and the reaction mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was then filtered off through a pad of celite. The filtrate was concentrated and the residue was dissolved in ethyl acetate (200 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . Removal of solvent under reduced pressure gave the crude product, which was then purified on silica gel column (methanol to ethyl acetate 5% to 12%) to afford the title compound (2.3 g, 85%).

Production Example 14

Step A

1- (t-butoxycarbonyl) -4-piperidone (6.75 g, 34 mmol) and sodium methoxide in a solution of commercially available 7-azaindole (2 g, 16.8 mmol) in methanol (20 mL) (21.6 mL, 100 mmol) of 25% methanol solution was added and the solution was heated under reflux for 2.5 h. The reaction solution was poured into 50 ml of ice water, extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated. The resulting residue was crystallized from n-hexane / ethyl acetate to give the compound (3.4 g, 67%).

Step B

To a solution of the title compound (1 g, 3.34 mmol) from Step A above in 65 ml of methanol was added 1 ml of acetic acid followed by 500 mg of 10% Pd / C. The mixture was stirred for 48 h under hydrogen atmosphere. The catalyst was filtered through celite and the solvent was removed under reduced pressure. The residue obtained was dissolved in ethyl acetate and washed with an aqueous solution of NaHCO ₃ . The organic phase was evaporated to give a yellowish compound which was purified using a Biotage flash chromatography system (ethyl acetate / n-heptane: 20-66%) to give a yellowish compound (0.92 g, 91%).

Step C

m-chloroperbenzoic acid (0.568 g, 1.69 mmol) was added to a cold solution (0 ° C.) of the title compound (0.51 g, 1.69 mmol) from Step B above in 20 mL of dichloromethane. The reaction mixture was warmed up to room temperature and then stirred for 12 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified using a Biotage flash chromatography system (methanol / dichloromethane: 3 to 10%) to give a white compound (0.4 g, 74%).

Step D

In a solution of the title compound (0.38 g, 1.19 mmol) from step C above in 24 mL of toluene, dissolved in hexamethyldisilazane (0.25 mL, 1.19 mmol) and 14 mL of toluene dissolved in 12 mL of toluene. Benzoyl bromide (0.42 ml, 3.59 mmol) was added simultaneously. The reaction mixture was stirred at rt for 12 h. The residue obtained after solvent evaporation was dissolved in 10 mL of methanol and treated with 3.5 mL of 1M sodium hydroxide solution. After stirring for 2 hours, saturated aqueous solution of citric acid (10 mL) was added. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with sodium bicarbonate and water and then dried. The residue obtained after solvent removal was purified using a Biotage flash chromatography system (methanol / dichloromethane: 1-5%) to give a white compound (0.185 g, 40% for 2 steps).

Step E

The title compound (0.1 g, 0.263 mmol) from Step D above was dissolved in N, N'-dimethylformamide (6 mL) and the solution was cooled to 0 ° C. Sodium hydride 95% (0.007 g, 0.289 mmol) was partially added at 0 ° C. After the addition was complete the mixture was stirred at rt for 1 h. Triisopropylsilylchloride (0.06 mL, 0.289 mmol) was then added and the mixture was stirred at rt for 19 h. The mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was used methanol / dichloromethane: 1-5% to give the title compound as a white solid (0.1 g, 71%).

Production Example 15

Step A

To a solution of the title compound (1 g, 2.63 mmol) from Preparation Example 14 Step D in dry tetrahydrofuran (25 ml) was partially added 60% sodium hydride (0.111 g, 2.89 mmol) at 0 ° C. The mixture was stirred at rt for 30 min and then methyl iodine (0.491 ml, 7.89 mmol) was added. After completion, it was checked by TLC plate and the solution was concentrated to dryness. The residue was purified by flash chromatography with 15% to 40% ethylacetate / n-heptane to give the compound as a white solid (0.984 g, 95%).

Step B

To a solution of the title compound (0.688 g, 1.745 mmol) from Step A above in dichloromethane (50 ml) was added 2 M hydrogen chloride in diethyl ether (8.72 ml, 17.45 mmol). The resulting mixture was stirred at rt for 12 h. The reaction mixture was concentrated to dryness to afford a beige solid compound (0.654 g, 99%).

Step C

To a solution of the title compound (0.654 g, 2.223 mmol) from Step B above in MeOH (50 ml), triethylamine (0.781 ml, 5.56 mmol), formaldehyde solution (0.196 ml, 2.445 mmol) and sodium triacetoxyboro Hydride (0.565 g, 2.67 mmol) was added sequentially. The resulting mixture was stirred at rt for 12 h. The mixture was concentrated to dryness, then the residue was diluted with water and ethyl acetate. Extraction was performed with NaOH 1 M and brine. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness to afford the desired compound as a yellowish solid (0.411 g, 60%).

Production Example 16

Step A

To a solution of the title compound (220 mg, 0.55 mmol) in MeOH (3 mL) was added 3N HCl in MeOH (0.5 mL) and the reaction mixture was stirred overnight. Removal of solvent under reduced pressure gave the title compound (180 mg, 98%).

Step B

To a solution of compound (220 mg, 0.75 mmol) in MeOH (5 ml) was added NaCNBH ₃ (200 mg, 3.1 mmol). The reaction mixture was stirred overnight. The solvent was removed and the crude product was purified on a silica gel column using a Biotage Isolera One purification system with MeOH / DCM gradients (1/99 => 5/95) to give the title compound (92 mg, 30%).

Preparation Example 17

Step A

To a solution of the title compound (0.500 g, 1.315 mmol) from Preparation Example 14 Step D in dichloromethane (10 ml) was added 2 M diethyl ether (3.29 ml, 6.57 mmol). The resulting mixture was stirred at rt for 12 h. After completion, the slurry was concentrated and dried to give the compound as a beige solid (0.443 g, 95%).

Step B

To a solution of the title compound (0.443 g, 1.255 mmol) and triethylamine (0.353 ml, 2.509 mmol) from step A in methanol (5 ml) followed by formaldehyde solution (0.121 ml, 1.506 mmol) followed by sodium triacetoxybo Low hydride (30.99 g, 1.882 mmol) was added. The resulting mixture was stirred at rt for 12 h. The mixture was concentrated to dryness, then the residue was diluted with water and ethyl acetate. Extraction was performed with NaOH 1M and brine. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness to afford the desired compound as a white solid (0.328 g, 89%).

Step C

To a solution of the title compound (0.328 g, 1.115 mmol) from Step B above in dry tetrahydrofuran (10 ml) was added partly 60% sodium hydride (0.045 g, 1.171 mmol). The resulting mixture was stirred at rt for 30 min, then triisopropylsilyl chloride (0.255 ml, 1.204 mmol) was added. The reaction mixture was further stirred at rt for 3 h. The reaction mixture was concentrated to dryness and the residue was then purified by flash chromatography in DCM / MeOH 97: 3 to 90:10 to afford the desired compound as a white amorphous solid (0.184 g, 37%).

Production Example 18

Step A

Commercially available 6-nitroindole (2.15 g, 13.27 mmol) was dissolved in methanol (10 mL) and commercially available N-Boc-4-piperidone (3.93 g, 19.8 mmol) was added. After addition of a 25% solution of sodium methoxide in methanol (8.22 mL, 38 mmol), the mixture was heated in ˜100 ° C. overnight in a sand-bath. The mixture was diluted with ethyl acetate (150 mL) and washed with saturated sodium bicarbonate (40 mL) and brine (40 mL). The organic phase was separated, dried over Na ₂ SO ₄ and filtered to remove solvent. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (40/60) to elute the starting material and then purified by ethyl acetate / n-heptane (60/40) to give the title compound as a yellow solid. Was obtained (2.56 g, 56%).

Step B

To a solution of the title compound (2.2 g, 6.3 mmol) from Step A above in tetrahydrofuran (50 mL) was added sodium hydride (0.18 g, 7.56 mmol). The dark suspension was stirred for 10 minutes, then triisopropylsilyl chloride (1.24 g, 6.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. At this time, the reaction mixture was quenched with water and concentrated. The resulting residue was dissolved in EtOAc (300 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to give the crude product which was then purified on a silica gel column to give the title compound (1.5 g, 46%).

Step C

To a solution of the title compound (1.5 g, 3.0 mmol) from Step B above in ethyl acetate (50 mL) was added 10% Pd / C. The mixture was degassed under vacuum and refilled with hydrogen. The reaction mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and the solvent evaporated. The residue was then purified by chromatography on silica using ethyl acetate / n-heptane gradient (20/80-> 50/50) to give the title compound as a solid (0.51 g, 36%).

Preparation Example 19

Step A

Preparation Example 17 The title compound (0.93 g, 2.71 mmol) from Step A was dissolved in N, N'-dimethylacetamide (10 mL) and the mixture was cooled to 0 ° C. Sodium hydride (0.085 g, 3.45 mmol) was added at 0 ° C. and the mixture was stirred at 0 ° C. for 5 minutes and then at room temperature for 15 minutes. Methyl iodine (0.175 mL, 2.72 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate (100 mL) and water (30 mL). The organic phase was separated, dried over Na ₂ SO ₄ and filtered to remove solvent. The residue was purified using Biotage system with ethyl acetate / n-heptane gradient (5/95-> 40/60) to afford the title compound as a yellow solid (0.87 g, 90%).

Step B

To a solution of the title compound (0.87 g, 2.44 mmol) from Step A above in ethanol (50 mL) was added 10% Pd / C catalyst (0.4 g). The mixture was degassed under vacuum and refilled with hydrogen. The reaction mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered off and the solvent was evaporated. The residue was purified using a Biotage system with ethyl acetate / n-heptane gradient (5/95-> 100/0) to give the title compound as a pale pink foam (0.3 g, 38%).

Production Example 20

Step A

Commercially available 6-nitroindole (2.15 g, 13.27 mmol) was dissolved in methanol (15 mL) and commercially available N-methyl-4-piperidone (2.19 mL, 19.8 mmol) was added. After addition of a 25% solution of sodium methoxide in methanol (8.22 mL, 38 mmol), the mixture was heated in a sand-batch at ˜100 ° C. for 30 h. The mixture was diluted with water (100 mL) and stirred at rt for 10 min. The precipitate was collected by filtration, washed with methanol (25 mL) and air-dried to give the title compound as an orange solid (2.47 g, 72%).

Step B

To a solution of the title compound (1.1 g, 4.32 mmol) from Step A above in tetrahydrofuran (25 mL) was added sodium hydride (0.136 g, 5.5 mmol) at 0 ° C. The dark suspension was stirred at 0 ° C. for 5 minutes and at room temperature for 15 minutes. Triisopropylsilyl chloride (0.58 mL, 4.35 mmol) was then added. The reaction mixture was stirred at ˜85 ° C. for 2 hours in a sand-bath. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated bicarbonate (25 mL) and brine (25 mL). The organic phase was separated, dried over Na ₂ SO ₄ and filtered to remove the solvent to give a mixture of starting material and the title compound. This mixture was used directly in the next step.

Step C

To a solution of the mixture from step B above in ethanol (30 mL) was added 10% Pd / C catalyst (0.4 g). The mixture was degassed under vacuum and refilled with hydrogen. The reaction mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered off and the solvent was evaporated. The residue was then purified by chromatography on silica using dichloromethane / methanol (9/1) to afford a mixture of the title compound with compounds that did not reduce double bonds (0.22 g). This mixture was hydrogenated again in ethanol (15 mL) using 10% Pd / C catalyst (0.11 g) as described above. Filtration of the solution and evaporation of the solvent gave the title compound as colorless glass (0.2 g, 19% for two steps).

Production Example 21

Step A

Commercially available 4-amino benzoic acid (5 g, 36 mmol) was dissolved in 1 M sodium hydroxide solution (40 mL, 40 mmol) and 1,4 dioxane (30 mL). After di-tert-butyl dicarbonate (7.85 g, 36 mmol) was added, the mixture was stirred at rt over the weekend. Dioxane was removed in vacuo and the residue was diluted with water (100 mL). Concentrated hydrochloric acid (-37%) was then added until pH-3. The precipitate was collected by filtration, washed with water (100 mL) and air-dried to give the title compound as a white solid (6.3 g, 72%).

Step B

The title compound (0.43 g, 1.8 mmol) from step A was suspended in tetrahydrofuran (10 mL) and treated with carbonyldiimidazole (0.37 g, 2.26 mmol). The mixture was stirred at room temperature for 1 hour. To the clear solution was then added a solution of dimethylamine 2 M in tetrahydrofuran (2.25 mL, 4.5 mmol). Stirring was continued overnight and the solvent was removed. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% citric acid solution in brine (15 ml) and water (15 ml). The organic phase was separated, dried over Na ₂ SO ₄ and filtered to remove the solvent to afford the title compound as a colorless foam. (0.46 g, 96%).

Step C

The title compound (0.46 g, 1.75 mmol) from step B above was dissolved in dichloromethane (2.2 mL) and treated with a 4M solution of hydrochloric acid in 1,4-dioxane (2.2 mL, 8.8 mmol). The mixture was stirred at rt for 3 h and diluted with ethyl acetate (20 mL). Saturated aqueous sodium carbonate was then added until pH-10. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate to give the title compound as an off white solid (0.16 g, 55%).

Preparation Example 22

Step A

Commercially available 3-amino benzoic acid (5 g, 36 mmol) was dissolved in 1 M sodium hydroxide solution (40 mL, 40 mmol) and 1,4-dioxane (30 mL). After di-tert-butyl dicarbonate (7.85 g, 36 mmol) was added, the mixture was stirred at rt over the weekend. Dioxane was removed in vacuo and the residue was diluted with water (100 mL). Concentrated hydrochloric acid (-37%) was then added until pH-3. The precipitate was collected by filtration, washed with water (100 mL) and air dried to give the title compound as a white solid (7.3 g, 84%).

Step B

The title compound (0.43 g, 1.8 mmol) from step A was suspended in tetrahydrofuran (10 mL) and treated with carbonyldiimidazole (0.37 g, 2.26 mmol). The mixture was stirred at room temperature for 1 hour. To the clear solution was then added a solution of dimethylamine 2 M in tetrahydrofuran (2.25 mL, 4.5 mmol). Stirring was continued overnight and the solvent was removed. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% citric acid solution in water (15 mL) and brine (15 ml). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed to afford the title compound as a colorless foam (0.36 g, 75%).

Step C

The title compound (0.36 g, 1.37 mmol) from Step B above was dissolved in dichloromethane (2 mL) and treated with a 4M solution of hydrochloric acid in 1,4-dioxane (2 mL, 8 mmol). The mixture was stirred at rt for 3 h and diluted with ethyl acetate (20 mL). Saturated aqueous sodium carbonate was then added until pH-10. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate to give the title compound as an off white solid (0.08 g, 36%).

Preparation Example 23

Step A

To a suspension of the title compound (2 g, 6.92 mmol) from Preparation Example 3 Step A in dry acetonitrile (15 mL) was added dimethylsulfate (0.885 g, 6.92 mmol). The reaction mixture was heated at 70 ° C. for 8 hours. The clear solution was then cooled to room temperature. The solution was partitioned into three sealed tubes and cooled to 0 ° C. under argon atmosphere. A solution of 4-amino piperidine-1-carboxylic acid tert-butyl ester (0.1 g) in methanol (5 mL) was then added to each sealed tube and heated at 50-60 ° C. for over 2 days. Solvent was removed and the residue was dissolved in ethyl acetate (200 mL). The organic phase was washed with diluted Na ₂ CO ₃ solution, water and brine and dried over Na ₂ SO ₄ . The solvent was evaporated and the crude product was purified on silica gel (EtOAc) to give the title compound (0.130 g).

Preparation Example 24

Step A

Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (˜50-60%) was added. . The mixture was heated at ˜115 ° C. for 18 h in a sand-bath. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate / n-heptane (60/40) to give the title compound as an off-white solid (3.05 g, 93%).

Step B

The title compound (0.84 g, 4.49 mmol) from step A above was dissolved in ethanol (16 mL) and water (4 mL). Cyclohexanone (0.54 mL, 5.1 mmol) was added and the mixture was stirred at rt for 1 h. The precipitate was collected by filtration, washed with ethanol (5 mL) and air-dried to give the title compound as a white solid (0.88 mg, 73%).

Step C

The title compound (0.2 g, 0.75 mmol) from Step B was suspended in diethylene glycol (2 mL) and heated at 250 ° C. for 30 minutes using a Biotage Initiator microwave. The mixture was diluted with ethyl acetate (40 mL) and water (15 mL). The organic phase was separated, washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered and the solvent removed. The residue was purified using Biotage Isolera One system with ethyl acetate / n-heptane (5/95-> 30/70) gradient to afford the title compound as an off-white solid (0.096 mg, 51%).

Step D

The title compound (0.06 g, 0.24 mmol) from Step C above was suspended in ethylene glycol (2 mL) and 30% ammonium hydroxide solution (3 mL). After adding copper (I) -oxide (0.005 g, 0.035 mmol), the mixture was heated at 150 ° C. for 45 minutes using a Biotage Initiator microwave. The reaction mixture was diluted with ethyl acetate (30 mL) and a mixture of water / ammonium hydroxide (10 mL, 1/1). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent evaporated. Purification of the residue by (95/5) PREP-TLC using dichloromethane / methanol gave the title compound as a brown solid (0.022 g, 50%).

Preparation Example 25

Step A

To a solution of the title compound (1 g, 5.37 mmol) from Preparation Example 23 step A in ethanol (50 mL) was added cyclopentanone (0.45 g, 5.37 mmol) and the reaction mixture was stirred at rt for 3 h. At this time, the solvent was removed under reduced pressure to give the title compound (1.36 g, quantitative).

Step B

A solution of the title compound (0.65 g, 2.55 mmol) from Step B above in diethylene glycol (11 mL) was sealed in a microwave applicable glass tube (20 mL). The reaction mixture was then heated at 250 ° C. for 90 minutes using microwave. The reaction mixture was cooled and poured into ethyl acetate (120 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to afford the crude product which was purified on a silica gel column (dichloromethane) to give the title compound (0.120 g, 20%).

Step C

The title compound (0.1 g, 0.42 mmol) from step C above was dissolved in diethylene glycol (2 mL) and 25% ammonium hydroxide solution (3 mL) and copper (I) -oxide (0.008 g, 0.058 mmol) Was added. The reaction mixture was then heated at 150 ° C. for 90 minutes using Biotage Initiator microwaves. The reaction mixture was diluted with dichloromethane (200 mL) and washed with water and brine solution. The organic phase was separated and dried over Na ₂ SO ₄ . The residue was purified on silica gel column (1/10, methanol / dichloromethane) to give the title compound (0.06 g, 83%).

Preparation Example 26

Step A

To a suspension of 2-6-dibromopyridine (5 g, 21.11 mmol) in ethanol (50 mL) was added methylhydrazine (3.33 mL, 63.3 mmol). The resulting mixture was heated to 100 ° C. for 20 hours. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (2 ×) using ethyl acetate / n-heptane (15% to 35%). The product was obtained as a light reddish liquid (2.1 g, 49%).

Step B

To a mixture of the title compound (0.500 g, 2.475 mmol) and cyclohexanone (0.256 ml, 2.475 mmol) from step A was added ethanol (ratio: 1.000, volume: 10.00 ml). The resulting solution was stirred for 2 hours at room temperature and then the solvent was removed under vacuum. Solvent was removed. Under vacuum. The oil was diluted with diethylene glycol (ratio: 1.000, volume: 10 ml) and the resulting mixture was heated by microwave at 250 ° C. for 35 minutes. The dark solution was poured into water and filtered. The solid was purified by flash chromatography in ethyl acetate / n-heptane (10% to 30%) to give the expected compound as a white solid (0.307 g, 47%).

Preparation Example 27

Step A

Preparation Example 25 To a mixture of the title compound (0.500 g, 2.475 mmol) and cyclopentanone (0.208 g, 2.475 mmol) from Step A was added ethanol (ratio: 1.000, volume: 10.00 ml). The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under vacuum. The oil was diluted with diethylene glycol (ratio: 1.000, volume: 10 ml) and the resulting mixture was heated by microwave at 250 ° C. for 35 minutes. The dark solution was poured into water and filtered. The solid was purified by flash chromatography in ethyl acetate / n-heptane (10% to 30%) to give the expected compound as a yellowish solid (0.264 g, 42%).

Preparation Example 28

Step A

Commercially available 1,4-cyclohexadione monoethylene acetal (5 g, 32 mmol) was dissolved in methanol (65 mL) and the mixture was placed in a cold-water bath. Sodium borohydride (1.9 g, 50 mmol) was added in small portions (exotherm). After the addition was complete, the mixture was stirred at rt for 2 h. The solvent was removed and the residue was dissolved in ethyl acetate (150 mL), water (40 mL) and 1 M NaOH (10 mL). The organic phase was separated and the aqueous phase and the aqueous phase extracted with ethyl acetate (4 x 75 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed to give the title compound as a colorless liquid (4.8 g, 94%).

Step B

Triphenylphosphine (12.57 g, 48.6 mmol) and phthalimide (3.56 g, 24.22 mmol) were dissolved in tetrahydrofuran (90 mL) and the mixture was cooled to 0 ° C. At 0 ° C., a solution of the title compound (3.84 g, 24.2 mmol) from Step A above in tetrahydrofuran (90 mL) is added, followed by ˜diethyl azodicarboxylate in toluene (19.9 mL, 48.6 mmol). 40% -solution was added. The mixture was stirred at 0 ° C. for 10 minutes and then at room temperature overnight. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate / n-heptane (20/80) as mobile phase to give the title compound as an off-white solid (3.5 g, 50%).

Step C

The title compound (3.5 g, 12.1 mmol) from step B was suspended in tetrahydrofuran (30 mL) and water (20 mL). After p-toluene sulfonic acid (0.13 g, 0.67 mmol) was added, the mixture was heated at ˜115 ° C. for 2 hours in a sand-bath. The mixture was diluted with ethyl acetate (200 mL) and aqueous sodium bicarbonate solution was added until pH-8-9. The organic phase was separated and the aqueous phase extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed to give the title compound as an off white solid (3 g, quantitative).

Step D

Preparation Example 23 The title compound from Step A (1.54 g, 8.23 mmol) was dissolved in ethanol (50 mL) and the title compound from Step C (2 g, 8.23 mmol) was added. The mixture was stirred at rt for 1 h to form a suspension. Solvent was removed to give the title compound as an off white solid (3.3 g, quant.).

Step E

The title compound (1 g, 2.42 mmol) from Step D above was suspended in diethylene glycol (10 mL) and heated at 250 ° C. for 35 minutes using a Biotage Initiator microwave. The reaction mixture was diluted with ethyl acetate (100 mL) and brine (20 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The reaction was performed two more times as described above and the combined crude product was treated with methanol (15 mL). The precipitate was collected by filtration, washed with methanol (5 mL) and air-dried to give the title compound as a beige solid (1.57 g, 49%).

Step F

The title compound (1.57 g, 3.96 mmol) from Step E above was suspended in ethanol (50 mL) and treated with a 50-60% aqueous solution of hydrazine-hydrate (12 mL, 119 mmol). The mixture was stirred overnight at room temperature to give a clear solution. Solvent was removed and the residue was treated with dichloromethane (150 mL). The mixture was sonicated for 5 minutes and then stirred at room temperature for 30 minutes. The precipitate was collected by filtration and washed with dichloromethane (15 mL). The combined filtrates were evaporated to afford the title compound as a beige solid (0.74 g, 70%).

Step G

The title compound (0.87 g, 3.28 mmol) from step F above was dissolved in tetrahydrofuran (60 mL) and treated with triethylamine (1.1 mL) and di-tert-butyl dicarbonate (2.7 g, 12.4 mmol) It was. The mixture was heated in ˜40 ° C. overnight in a sand-bath. Solvent was removed and the residue was treated with diethyl ether (20 mL). The precipitate was collected by filtration and the solid was washed with diethyl ether (10 mL) to give a mono-Boc protected intermediate as a white solid (0.86 g). The filtrate was evaporated to afford the crude title compound. The mono-Boc intermediate (0.86 g) was dissolved in tetrahydrofuran (60 mL) and treated with triethylamine (2.2 mL) and di-tert-butyl dicarbonate (5.4 g, 24.8 mmol). The mixture was stirred at rt overnight, the solvent was removed and the crude product combined with the material from the first run. Purification of the crude product on silica using the Biotage Isolera One system using ethyl acetate / n-heptane gradient (5/95-> 30/75) gave the title compound as a white solid / foam (1.16 g, 76%).

Step H

The title compound (1.16 g, 2.5 mmol) from Step G above was dissolved in N, N'-dimethylacetamide (8 mL) and the mixture was cooled to 0 ° C. At 0 ° C., sodium hydride (0.07 g, 3 mmol) was added and the mixture was stirred at 0 ° C. for 1 h. Methyliodine (0.2 mL, 3.32 mmol) was added at 0 ° C. and the mixture was stirred at rt for 2 h. The mixture was diluted with ethyl acetate (80 mL) and brine (20 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using Biotage Isolera One system with ethyl acetate / n-heptane gradient (5/95-> 15/85) to give starting material (0.23 g, 20%) and the corresponding N ^The title compound was obtained as a colorless foam with ¹ -methyl-derivative (0.053 g, 5%, white solid) (0.73 g, 61%),

Step I

The title compound (0.88 g, 1.83 mmol) from step H above was dissolved in tetrahydrofuran (15 mL) and methanol (15 mL). After adding 1 M sodium hydroxide solution (15 mL, 15 mmol), the mixture was stirred at rt overnight. The organic solvent was removed and the residue was diluted with water (20 mL). The precipitate was collected by filtration, washed with water (5 mL) and air-dried to give the title compound as a white solid (0.67 g, 96%).

Step J

The title compound (0.38 g, 0.89 mmol) from step I above was suspended in tetrahydrofuran (5 mL) and the mixture was cooled to 0 ° C. At 0 ° C., sodium hydride (0.028 g, 1.15 mmol) was added and the mixture was stirred and stirred at 0 ° C. for 5 minutes and at room temperature for 15 minutes to make a clear solution. After addition of triisopropylsilyl-chloride (0.12 mL, 0.9 mmol), the mixture was heated in ˜85 ° C. for 1 hour in a sand bath. The mixture was diluted with ethyl acetate (50 mL) and brine (15 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using the Biotage Isolera One system using ethyl acetate / n-heptane gradient (5/95-> 100/0), with starting material (0.14 g, 39%, white Solid) The title compound was obtained as a colorless oil (0.27 g, 52%).

Preparation Example 29

Step A

To a solution of commercially available 4-bromophenyl hydrazine (1.46 g, 6.5 mmol) in ethanol (50 mL) was added the material of Preparation Example 28 Step C (1.6 g, 6.5 mmol) in ethanol (15 mL). . The reaction mixture was stirred at room temperature for 2 hours. Solvent was removed to give the title compound as a solid (2.9 g, quant.).

Step B

A solution of the title compound (2.9 g, 7.0 mmol) from Step A in diethylene glycol (45 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction tube was then heated to 250 ° C. using microwave for 55 minutes. The reaction was carried out in three batches. The combined reaction mixture was collected, dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the crude product which was purified on a silica gel column (ethyl acetate / n-heptane 20% -40%) to give the title compound (2.1 g, 72 %).

Step C

To a stirred solution of compound (2 g, 5.0 mmol) from Step B in THF (50 mL) was added NH ₂ NH ₂ .H ₂ O (500 mg 10 mmol) and the reaction mixture was stirred overnight. The precipitate was filtered off, the filtrate was concentrated and used in the next step without further purification and characterization.

Step D

To compound (2.01 g) from Step C in THF (50 mL) was added (Boc) ₂ O (2 g, 9.1 mmol) and triethylamine (1 g, 10 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed and the crude product was crystallized from an ethyl acetate and heptane mixture to give a mono-Boc derivative (1.15 g). The crystallized mono-Boc derivative was dissolved in THF (50 mL), excess (Boc) ₂ O (5 g, 22.9 mmol) and triethylamine (1.5 ml) were added and the reaction mixture was stirred for 2 days. The solvent was removed and the crude product was purified on silica gel column chromatography (ethyl acetate / n-heptane 10-20%) to give the title compound (1.35 g).

Step E

The solution of the title compound (370 mg, 0.79 mmmol) from Step D in DMA (7 mL) was cooled to ice bath temperature and then NaH (40 mg, 1.59 mmol) was added in part. The reaction mixture was stirred at rt for 30 min, cooled to ice bath temperature and methyl iodine (222 mg, 1.59 mmol) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was dissolved in dichloromethane (250 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed and the residue was purified by silica gel column chromatography (0/100 to 15/85; EtOAc / heptane mixture) to give the title compound as a white foam (271 mg, 71%).

Production Example 30

Step A

Commercially available 4-aminocyclohexanol hydrogen chloride salt (25 g, 164 mmol) was dissolved in water (350 mL). Potassium carbonate (72 g, 328 mmol) was then added followed by a solution of commercially available N-carbethoxyphthalimide in tetrahydrofuran (300 mL). The reaction mixture was then stirred vigorously for 3 days at room temperature. Tetrahydrofuran was evaporated under reduced pressure and the remaining aqueous phase was extracted with dichloromethane (2 x 300 mL) until the aqueous phase became clear. The combined organic phases were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated under reduced pressure to give the title compound as a white solid (28 g, 69%).

Step B

The title compound (28 g, 114 mmol) from Step A above was dissolved in dichloromethane (990 mL) and pyridinium chlorochromate (33.6 g, 157 mmol) was partially added. The reaction mixture was stirred at rt for 8 h. Then another batch of pyridinium chlorochromate (10.4 g, 48.6 mmol) was added in part and stirring at room temperature was continued for 18 hours. The reaction mixture was filtered through a pad of celite and the pad of celite was washed with dichloromethane (400 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by chromatography on silica using ethyl acetate / n-heptane (60/40) as mobile phase to give the title compound as a white solid (24.62 g, 88 %)

Step C

Preparation Example 23 The title compound from Step A (19 g, 101 mmol) was dissolved in ethanol (570 mL) and the title compound from Step B (24.6 g, 101 mmol) was added. The mixture was stirred at rt for 2 h to form a suspension. Solvent was removed to give the title compound as an off white solid (41.8 g, quant.).

Step D

The title compound (1.3 g, 3.15 mmol) from Step C above was suspended in diethylene glycol (13 mL) and heated at 245 ° C. for 35 minutes using a Biotage Initiator microwave. The reaction mixture was diluted with water (90 mL) and the precipitate was collected by filtration and air dried. This reaction sequence was repeated until the title compound (41.8 g) from step C was used up to afford the title compound as a gray solid (34.2 g, 85%). The crude material was used directly in the next step.

Step E

The title compound (34.2 g, 86.36 mmol) from Step D above was suspended in ethanol (1080 mL) and treated with a 50-60% aqueous solution of hydrazine-hydrate (185 mL, 1990 mmol). The mixture was stirred at rt for 2 days. The precipitate was separated by filtration and washed with ethanol (150 mL). The combined filtrates were concentrated to ˜150 mL and extracted with dichloromethane (2 × 450 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and the solvent removed to give the crude title compound as dark solid (22.97 g, weight).

Step F

The title compound (22.97 g, 90.1 mmol) from step E above was dissolved in tetrahydrofuran (1000 mL) and treated with triethylamine (64 mL) and di-tert-butyl dicarbonate (79 g, 367 mmol) It was. The mixture was stirred at rt for 18 h and the solvent was removed under reduced pressure. The residue was treated with diethyl ether (600 mL) and stirred at rt for 30 min. The precipitate was collected by filtration, washed with diethyl ether (250 mL) and air-dried to give the title compound as a white solid (11 g, 33%):

Preparation Example 31

Step A

Preparation Example 30 The title compound from Step F (11 g, 30 mmol) was dissolved in N, N'-dimethylacetamide (140 mL) and the mixture was cooled to 0 ° C. At 0 ° C., sodium hydride (2.2 g, 92 mmol) was added and the mixture was stirred at 0 ° C. for 2 hours. Methyl iodine (9 mL, 145 mmol) was then added and the mixture was stirred at 0 ° C. for 5 minutes. The ice bath was removed and fever was observed after 5 minutes. The reaction mixture was briefly placed in a water bath and stirred overnight at room temperature. The reaction mixture was diluted with water (700 mL) and the precipitate was collected by filtration. Further purification of the solid material by chromatography on silica using dichloromethane / acetone (98/2) gave the title compound as a white solid (10.6 g, 85%).

Step B

The title compound (0.1 g, 0.253 mmol) from Step A above was dissolved in dichloromethane (2 mL) and treated with a 2 M solution of hydrogen chloride (0.5 mL, 1 mmol) in diethylether. The mixture was stirred at room temperature overnight. Triethyl amine (0.07 mL, 0.316 mmol) and acetyl chloride (0.316 mL, 1.034 mmol) were then added to the reaction mixture. Stirring was continued for an additional 2 hours, then the mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium carbonate. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and solvent removed to give a residue, which was purified using Biotage flash chromatography system (methanol / dichloromethane: 0-> 5%) to give the title compound. Was obtained as a white solid (0.065 g, 75% for 2 steps).

Preparation Example 32

Step A

To a suspension of commercially available 2,6-dibromopyridine (10 g, 42.2 mmol) in ethanol (50 mL) was added commercially available methylhydrazine (11.11 mL, 211 mmol). The mixture was heated at 80 ° C. (reaction mixture temperature) for 48 hours. The reaction mixture is concentrated to dryness and the residue is purified by chromatography on silica using the Biotage Isolera One purification system using ethyl acetate / n-heptane gradient (15/75-> 35/65) to reddish the title compound. Obtained as an oil, which was placed at room temperature to make a solid (7.6 g, 89%).

Step B

The title compound (3 g, 14.8 mmol) from Step A and dimer commercially available 4- (methylamino) cyclohexanone-2,2-dimethyltrimethylene ketal hydrochloride (3.7 g, in dioxane (30 mL) 14.8 mmol) was placed in an ice bath. To the stirred suspension was concentrated H ₂ SO ₄ (3 mL) slowly. After the addition of H ₂ SO ₄ was complete, the reaction mixture was heated at reflux for 5 hours using a sand bath (˜140 ° C.). The reaction mixture was cooled to room temperature, the dioxane layer was discarded and ice water (20 mL) was added. The mixture was stirred until the sticky material dissolved. The pH of the reaction mixture was then adjusted to pH = 14 using aqueous NaOH solution. The aqueous layer was extracted with dichloromethane (200 mL) and the organic phase was washed with water and brine. The organic phase was separated, dried over Na ₂ SO ₄ and the solvent removed under reduced pressure to give the crude title compound as an off white solid (4.7 g, quant.).

Step C

To a solution of the crude title compound (4.7 g) from Step A above in tetrahydrofuran (50 ml) was added triethylamine (5 mL) and di-tert-butyl dicarbonate (10 g, 45.8 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then concentrated and the residue was dissolved in dichloromethane (200 mL). The organic phase was washed with water, brine and dried over Na ₂ S0 ₄ . The organic solvent was removed under reduced pressure and the residue was purified on silica gel using Biotage Isolera One purification system with ethyl acetate / n-heptane gradient (20/80-> 50/50) to afford the title compound as a white solid. (3.55 g, 61 for step 2).

Preparation Example 33

Step A

Commercially available 4-hydroxy-cyclohexane carboxylic acid ethyl ester (10.32 g, 59.92 mmol) was dissolved in N, N'-dimethylformamide (50 mL) and imidazole (8.16 g, 119.5 mmol) was added. . Triisopropylsilylchloride (14.1 mL, 65.9 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with diethyl ether (150 mL) and washed with 1 M hydrochloric acid solution (150 mL). The organic phase was separated and the aqueous phase extracted with diethyl ether (150 mL). The combined organic phases were washed with 1 M hydrochloric acid solution (150 mL) and brine (150 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and the solvent removed to give the crude title compound as a colorless liquid (18.7 g, 95%).

Step B

The crude title compound (18.7 g, 65.17 mmol) from step A above was dissolved in tetrahydrofuran (90 mL) and methanol (60 mL). Lithium hydroxide hydrate (5.47 g, 130.6 mmol) was added and then the reaction mixture was heated for 2 h at ˜70 ° C. and overnight at rt using a sand-bath. Solvent was removed and the residue was dissolved in water (100 mL). The pH of the reaction mixture was adjusted to pH ˜3-4 with 1 M hydrochloric acid and the aqueous phase was extracted with ethyl acetate (2 × 200 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed to give the crude title compound as a pale yellow oil (16.65 g, 97%).

Step C

Diisopropylamine (9 mL, 65 mmol) was dissolved in tetrahydrofuran (100 mL) and the mixture was cooled to 0 ° C. At 0 ° C., n-butyllithium 1.6 M solution in n-hexane (38.5 mL, 61.6 mmol) was added and the reaction mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was then cooled to -78 ° C and a solution of crude title compound (8.3 g, 30.9 mmol) from Step B above in tetrahydrofuran (30 mL) was added dropwise. After the addition was complete, the cooling bath was removed and the reaction mixture was heated in a sand bath at −60 ° C. for 2 hours. The reaction mixture was again cooled to -78 ° C and methyl iodine (2.1 ml, 34 mmol) was added. The reaction mixture was stirred at -78 ° C for 2 hours and then warmed up to room temperature overnight. The reaction mixture was added to a mixture of diethyl ether (500 mL) and 1 M hydrochloric acid (500 mL). The organic phase was separated and the aqueous phase extracted with diethyl ether (2 x 200 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed. Purify the residue by chromatography on silica using ethyl acetate / n-heptane / methanol (15/84/1) as the mobile phase to give the title compound as a pale yellow oil (4.35 g, 50%), starting material Was recovered as a pale yellow oil (1.51 g, 18%).

Recovered Starting Material:

Step D

The title compound (2.18 g, 6.92 mmol) from step C above was dissolved in toluene (25 mL) and triethylamine (1.08 mL, 7.7 mmol) was added. After addition of diphenyl-phosphoryl azide (1.63 mL, 7.54 mmol), the reaction mixture was heated in a sand-bath at ˜115 ° C. for 1 hour until the development of nitrogen was complete. The mixture was cooled to 0 ° C. and washed with saturated sodium bicarbonate (15 mL), water (15 mL) and brine (15 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude isocyanate intermediate. The crude intermediate was dissolved in N, N'-dimethylacetamide (10 mL) and potassium tert-butoxide (0.8 g, 7.13 mmol) was added in part. After the addition was complete, the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate (80 mL) and water (30 mL). The organic phase was separated and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (10/90) as the mobile phase to give the title compound as a colorless oil (1.57 g, 59%).

Step E

The title compound (1.45 g, 3.77 mmol) from Step D above was dissolved in acetonitrile (25 mL) and 1M solution of tetra-butyl ammonium fluoride in tetrahydrofuran (14.8 mL, 14.8 mmol) was added. The reaction mixture was stirred overnight at room temperature and the solvent was removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (80/20) to give the title compound as a colorless oil (0.86 g, 99%).

Step F

The title compound (0.86 g, 3.76 mmol) from Step E above was dissolved in dichloromethane (40 mL) and pyridinium chlorochromate (1.18 g, 5.48 mmol) was partially added. The reaction mixture was stirred at rt for 18 h, filtered through a pad of celite and the celite was washed with dichloromethane (20 mL). The combined filtrates under reduced pressure were concentrated and the residue was purified by chromatography on silica using ethyl acetate / n-heptane (60/40) as mobile phase to give the title compound as a colorless oil (0.76 g, 89 %).

Step G

Preparation Example 23 The title compound (0.63 g, 3.35 mmol) from Step A was dissolved in ethanol (20 mL) and the title compound (0.76 g, 3.35 mmol) from Step F above was added. The mixture was stirred at room temperature for 1 hour to give a clear solution. Removal of solvent gave the title compound as dark yellow oil (1.33 g, quant.).

Step H

The title compound (0.7 g, 1.76 mmol) from Step G above was dissolved in diethylene glycol (10 mL) and heated at 245 ° C. for 60 minutes using Biotage Initiator microwave (pressure: 10-11 bar). The reaction mixture was diluted with water (15 mL) and dichloromethane (40 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed to afford the crude title compound as dark oil. This process was repeated one more time and the combined crude material was used directly in the next step.

Step I

The crude title compound from step H above was dissolved in tetrahydrofuran (45 mL) and treated with triethylamine (1.7 mL) and di-tert-butyl dicarbonate (2 g, 9.3 mmol). The mixture was stirred at rt for 18 h and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica using a Biotage Isolera One purification system with ethyl acetate / n-heptane gradient (5/95-> 30/70) to give three different fractions.

Fraction I: bis-Boc derivative; Yellow oil (0.15 g, 9%)

Fraction II: title compound recovered from step G; Yellow oil (0.13 g, 9%)

Fraction III: mono-Boc title compound; Off-white solid (0.26 g, 19%)

Step J

The bis-Boc derivative (0.15 g, 0.32 mmol) from Step I above was dissolved in tetrahydrofuran (2.6 mL) and methanol (2.6 mL). After adding 1 M aqueous sodium hydroxide solution (2.6 mL, 2.6 mmol), the reaction mixture was stirred overnight at room temperature and the solvent was evaporated. The residue was treated with water (20 mL), the precipitate was collected by filtration, washed with water (5 mL) and air-dried to give the mono-Boc title compound from step I as a white solid (0.09 g). , 76%).

Step K

The mono-Boc title compound (0.35 g, 0.94 mmol) from step I above was dissolved in N, N'-dimethylacetamide (5 mL) and the mixture was cooled to 0 ° C. Sodium hydride (0.068 g, 2.8 mmol) was added at 0 ° C. and the mixture was stirred at 0 ° C. for 90 minutes. Methyl iodine (0.27 mL, 4.45 mmol) was then added at 0 ° C., the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using Biotage Isolera One system with ethyl acetate / n-heptane gradient (5/95-> 30/70) to give the title compound as a white solid (0.31 g, 81%). ).

Preparation Example 34

Step A

Preparation Example 28 The title compound (12 g, 75.9 mmol) from Step A was dissolved in dichloromethane (240 mL) and triethylamine (14.5 mL) was added. After adding benzoylchloride (12.7 g, 91.2 mmol), the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (80 mL) and 10% aqueous citric acid solution (2 x 80 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to afford the crude title compound as an oil.

Step B

The crude title compound from step A above was dissolved in tetrahydrofuran (85 mL) and water (250 mL). Then p-toluene sulfonic acid (1 g, 5.8 mmol) was added and the mixture was heated in a sand bath at ˜115 ° C. for 4 hours. The mixture was cooled to rt, diluted with ethyl acetate (250 mL) and the organic phase separated. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (20/80) as the mobile phase to give the title compound as a white solid (10.7 g, 64% for two steps).

Step C

Preparation Example 23 The title compound (3.69 g, 19.6 mmol) from Step A was dissolved in ethanol (85 mL) and the title compound (4.28 g, 19.6 mmol) from Step B above was added. The mixture was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the title compound as a yellow foam (7.6 g, quant.).

Step D

The title compound (0.95 g, 2.45 mmol) from Step C above was dissolved in diethylene glycol (9.5 mL) and heated at 245 ° C. for 35 minutes using a Biotage Initiator microwave. The reaction mixture was diluted with water (25 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (25 mL), dried over Na ₂ SO ₄ , filtered and the solvent removed. This process was repeated seven more times and the crude material bound on silica using dichloromethane / acetone (98/2) as the mobile phase was purified by chromatography to give the title compound as an off-white solid (3.4 g, 46%). ).

Step E

The title compound (3.4 g, 9.19 mmol) from Step D above was dissolved in N, N'-dimethylacetamide (40 mL) and the solution was cooled to 0 ° C. Sodium hydride (0.29 g, 11.95 mmol) was partially added at 0 ° C. The mixture was stirred at 0 ° C. for 1 h and methyl iodine (1.19 mL, 19.14 mmol) was added. The mixture was stirred at 0 ° C. for 5 minutes and then at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (250 mL), 10% aqueous citric acid solution (80 mL) and brine (50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using Biotage Isolera One purification system with ethyl acetate / n-heptane gradient (5/95-> 30/70) to give the title compound as an off-white solid (2.42 g, 68 %).

Step F

The title compound (0.33 g, 0.86 mmol) from Step E above was dissolved in tetrahydrofuran (8 mL) and water (8 mL). After adding potassium hydroxide (0.75 g, 13.4 mmol), the mixture was heated at 140 ° C. for 30 minutes using Biotage Initiator microwaves. The reaction mixture was diluted with ethyl acetate (30 mL) and water (10 mL). The organic phase was separated, washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and the solvent removed. This process was repeated six more times to give the title compound as an off white solid (1.74 g, 98%).

Step G

The title compound (0.2 g, 0.71 mmol) from Step F above was dissolved in N, N'-dimethylacetamide (3 mL) and the solution was cooled to 0 ° C. Sodium hydride (0.023 g, 0.92 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 1 h and methyl iodine (0.09 mL, 1.47 mmol) was added. The mixture was stirred at rt for 16 h. The reaction mixture was diluted with ethyl acetate (30 mL), 10% aqueous citric acid solution (8 mL) and brine (5 mL). The organic phase was separated, washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using the Biotage Isolera One purification system with ethyl acetate / n-heptane gradient (5/95->40/60-> 100/0) to give the title compound as a pale orange oil. Obtained, which was left at room temperature to make a solid (0.13 g, 63%).

Preparation Example 35

Step A

To a solution of commercially available 4-bromophenyl hydrazine (2.6 g, 11.6 mmol) in ethanol (50 mL) was added ketone derivative (2.54 g, 11.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. Solvent was removed to give the title compound as a solid (4.5 g, quant.). The compound was used without further purification in the next step.

Step B

A solution of the title compound (4.4 g, 11.3 mmol) from this step in diethylene glycol (45 mL) was sealed in three different microwave glass tubes (20 mL). The reaction tube was then heated at 250 ° C. for 55 minutes using microwave. The combined reaction mixture was collected, dissolved in DCM (200 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the crude product which was purified on a silica gel column (ethyl acetate / n-heptane 20% -30%) to give the title compound (1.77 g, 42%).

Step C

To a stirred solution of compound (200 mg, 0.54 mmol) from Step B above in THF (50 mL) was added NaH (25 mg, 1.0 mmol). The suspension was stirred for 10 minutes. Methyl iodine solution (75 mg, 0.5 mmol) was then added and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (100 mL). The organic phase was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed and the crude material was purified on a silica gel column (eluent: 10:90 EtOAc: heptanes) to afford the title compound (200 mg, 96%).

Step D

To a solution of compound (200 mg, 0.52 mmol) from Step C in THF: H ₂ O (1: 1, 8 mL) was added KOH (450 mg, 7.8 mmol). The reaction mixture was heated for 30 minutes using microwave. The reaction mixture was extracted with ethyl acetate (150 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was evaporated and the crude was purified on silica gel column (eluent: 10:90 EtOAc: heptane) to give the title compound (137 mg, 69%).

Step E

To a solution of compound (130 mg, 0.46 mmol) from Step D in THF (10 mL) was added NaH (22 mg, 0.92 mmol). The suspension was stirred at rt for 10 min. Methyl iodine solution (129 mg, 0.92 mmol) was then added and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched carefully with water and extracted with ethyl acetate (150 mL) (150 mL). The organic phase was washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed and purified on a silica gel column (eluent: 10:90 EtOAc: heptanes) to afford the title compound (115 mg, 85.8%).

Preparation Example 36

Step A

To a solution of commercially available 3-bromophenyl hydrazine (2 g, 9.1 mmol) in ethanol (50 mL) was added a ketone derivative (2 g, 9.1 mmol). The reaction mixture was stirred for 2 hours at room temperature. Solvent was removed to give the title compound as a solid (3.52 g, quant.). The product was used without further purification in the next step.

Step B

A solution of the title compound (3.5 g, 9.1 mmol) in diethylene glycol (12 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction mixture was then heated at 245 ° C. for 50 minutes using microwave. The reaction mixture was dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure, and the crude product was purified on silica gel column (ethyl acetate / n-heptane 10% -40%) to give two regioisomers (1.17, 32 %).

Regioisomer A (7-Bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl benzoate) (670 mg)

Regioisomer B (5-Bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl benzoate) (500 mg)

Step C

To a stirred solution of Regioisomer A compound (450 mg, 1.2 mmol) from Step 2 in THF (15 mL) was added NaH (58 mg, 2.4 mmol). The suspension was stirred for 10 minutes. Methyl iodine solution (338 mg, 2.4 mmol) was then added and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (200 mL). The organic phase was washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed and the crude was purified on silica gel column (ethyl acetate / n-heptane 10% -30%) to give the title compound (357 mg, 77.6%).

Step D

To a solution of compound (357 mg, 0.92 mmol) from step 3 in THF: H ₂ O (1: 1, 8 mL) was added KOH (450 mg, 7.8 mmol). The reaction mixture was heated at 140 ° C. for 30 minutes using microwave. The reaction mixture was extracted with ethyl acetate (150 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was evaporated and the crude was purified on silica gel column (ethyl acetate / n-heptane 10% -40%) to give the title compound (160 mg, 62%).

Step E

To a solution of compound (160 mg, 0.57 mmol) from step 4 in THF (5 mL) was added NaH (122 mg, 5.0 mmol). The suspension was stirred at rt for 10 min. Methyl iodine solution (400 mg, 2.83 mmol) was then added and the reaction mixture was stirred for 4 hours. The reaction mixture was then quenched carefully with water and extracted with ethyl acetate (150 mL). The organic phase was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed and purified on a silica gel column (acetate / n-heptane 10% -40%) to give the title compound (120 mg, 71.8%).

Preparation Example 37

Step A

To a solution of the title compound (5 g, 31.6 mmol) in THF (100 mL) was added NaH (1.2 g, 50 mmol). The suspension was stirred at rt for 10 min. Methyl iodine solution (5.5 g, 39 mmol) was added slowly and the reaction mixture was stirred for 3 hours. The reaction mixture was then quenched carefully with water and the reaction mixture was concentrated. The residue was dissolved in EtOAc (200 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified on a silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (15/85-> 50/50) to give the title compound (4.3 g, 80%).

Step B

To a solution of the title compound (6.4 g, 37.2 mmol) in THF: H ₂ O (1: 1; 50 mL) was added p-toluene sulfonic acid (640 mg, 3.86 mmol). The reaction mixture was heated at 100 ° C. overnight. The reaction mixture was extracted with ethyl acetate (200 mL) (200 mL). The organic phase was washed with water, brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was purified on a silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80-> 50/50) to give the title compound (4.2 g, 89%).

Step C

To a solution of 4-methoxycyclohexanone (1.4 g, 10.8 mmol) from Step B in ethanol (50 mL) was added (3-bromophenyl) hydrazine hydrochloride (2.4 g, 10.8 mmol). The reaction mixture was then stirred at rt for 4 h. The solvent was then removed under reduced pressure to give the title compound (3.1 g, quant.). The product was used without further purification in the next step.

Step D

A solution of the title compound (3.1 g, 10.4 mmol) from step D in diethylene glycol (12 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction mixture was then heated at 250 ° C. for 50 minutes using microwave. The reaction mixture was dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure, and the crude product was purified on a silica gel column using a Biotage Isolera One purification system with EtOAc / n-heptane gradients (20/80-> 30/70). Purification gave a mixture of two legoisomers (1.6 g, 53%).

Step E

To a solution of the title compound (1.4 g, 4.99 mmol) from Step D above in THF (30 mL) was added di-tert-butyl dicarbonate (1.3 g, 5.9 mmol) and a catalytic amount of dimethylamino pyridine (5 mg). . The reaction mixture was then stirred for 1 hour. The solvent was removed and the crude product was purified on a silica gel column using the Biotage Isolera One purification system with EtOAc / n-heptane gradient (5/95-> 25/75) to give two regioisomers (1.6 g, 53%). The fast eluting compound was Regioisomer A (700 mg, 37%) and the slow eluting compound was Regioisomer B (1.1 g 58%).

Regioisomer A: tert-butyl 5-bromo-3-methoxy-3,4-dihydro-1H-carbazole-9 (2H) -carboxylate:

Regioisomer B: tert-butyl 7-bromo-3-methoxy-3,4-dihydro-1H-carbazole-9 (2H) -carboxylate:

Preparation Example 38

Step A

A solution of the title compound (11 g, 70 mmol) in THF: H ₂ O (100 mL, 1: 1) was heated at 110 ° C. overnight. The reaction mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (5.2 g, 65%).

Step B

To a solution of 2-bromo-6- (1-methylhydrazinyl) pyridine (5.2 g, 25.7 mmol) in THF (50 mL) was added 4-hydroxycyclohexanone (3.1 g, 27.1 mmol). The reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure to give an oily compound (7.6 g, quantitative). The compound was used without further purification in the next step.

Step C

A solution of the title compound (7.65 g, 25.7 mmol) from step B in diethylene glycol (45 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction tube was heated at 250 ° C. for 55 minutes using microwave. The reaction was carried out in three batches. The combined reaction mixture was collected, dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the crude product which was purified on a silica gel column (ethyl acetate / n-heptane 20% -40%) to give the title compound (3.6, 50 %).

Preparation Example 39

Step A

To a solution of 2-fluoroethanol (0.32 mL, 5 mmol) in a pyridine and toluene (5 mL, 1: 1) mixture was added p-toluenesulfonyl chloride at 0 ° C. The reaction mixture was stirred overnight. The reaction mixture was dissolved in EtOAc (150 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified on a silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane (5/95 => 30/70) to afford the title compound as a colorless liquid (1.54 g, 67%).

Preparation Example 40

Step A

To a solution of the title compound (150 mg, 0.53 mmol) from Preparation Example 38 Step C in THF (15 mL) was added NaH (25 mg, 1.06 mmol) and the suspension was stirred for 5 minutes. Then a solution of compound (116 mg, 0.53 mmol) from step A was added. The reaction mixture was heated at 100 ° C. overnight. The reaction mixture was dissolved in EtOAc (100 ml), washed with water and brine and dried over Na ₂ SO ₄ . The product was purified on silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (10/90 => 20/80) to give the title compound (78 mg, 45%).

Preparation Example 41

Step A

To a solution of the title compound (5.6 g, 35.4 mmol) in 2-iodine propane (28 mL) was added Ag ₂ O (16 g, 69.2 mmol) and the reaction mixture was stirred for 4 days. The reaction mixture is then diluted with diethyl ether, filtered, the filtrate is concentrated under reduced pressure and silica gel using Biotage Isolera One purification system with EtOAc / n-heptane gradient (5/95 => 20/80) The crude product on the column was purified to give the title compound (2.6 g, 57% based on starting material recovery).

Step B

To a solution of the title compound (3 g, 15.0 mmol) from step A in THF: H ₂ O (20 mL, 1: 1) was added p-toluene sulfonic acid (0.5 g, 3 mmol) and the reaction mixture was overnight at 100 ° C. Heated. The reaction mixture was extracted with EtOAc (200 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . The solvent was removed and the crude product was purified on silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 50/50) to give the title compound (2.1 g, 91% ).

Step C

To a solution of commercially available 2-bromo-6- (1-methylhydrazinyl) pyridine (620, 3.06 mmol) in THF (5 mL) was added the ketone derivative (0.62 g, 3.06 mmol) from step B. . The reaction mixture was stirred for 2 hours at room temperature. The solvent was removed to give the title compound as an oily substance (1 g, quant.). The product was used in the next step without further purification.

Step D

A solution of the title compound (1 g, 3.9 mmol) from Step C in diethylene glycol (12 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction mixture was then heated at 245 ° C. for 50 minutes using microwave. The reaction mixture was dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure and the crude product on a silica gel column using the Biotage Isolera One purification system with EtOAc / n-heptane gradient (10/90 => 50/50) Was purified to give the title compound (258 mg, 26%).

Preparation Example 42

Step A

To a solution of commercially available 3-bromophenyl hydrazine (2.74 g, 12.2 mmol) in ethanol (100 mL) was added a ketone derivative (3 g, 12.2 mmol) in ethanol (50 mL). in ethanol (50 mL). The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed and the title compound was obtained as a solid (5 g, quant.). The product was used in the next step without further purification.

Step B

A solution of the title compound (5 g, 12.1 mmol) from Step A in diethylene glycol (12 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction mixture was then heated at 245 ° C. for 50 minutes using microwave. The reaction was carried out in three batches. The combined reaction mixture was dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure and the crude product on a silica gel column using the Biotage Isolera One purification system with EtOAc / n-heptane gradient (10/90 => 55/45) Purification of the title compound gave the title compound as two regioisomers (3.3 g, 70%).

Regioisomer A (1.9 g) (2- (7-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl) isoindolin-1,3-dione)

Regioisomeric B (1.4 g) (2- (5-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl) isoindolin-1,3-dione)

Step C

To a stirred solution of the Regioisomer A compound (980 mg, 2.48 mmol) from Step B above in THF (25 mL) was added NH ₂ NH ₂ (2 mL). The reaction mixture was stirred for 2 days. The solid was filtered off. The filtrate was concentrated under reduced pressure and the crude product was dissolved in DCM (200 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the crude product was used in the next step without further purification.

Step D

To the crude product (1.1 g) from this step in THF (25 mL) was added (Boc) ₂ O (4.5 g, 20.6 mmol) and triethylamine (2.5 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed and the crude product was purified on a silica gel column using the Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 50/50) to give the fast eluting compound di-Boc- (650 mg), and slow eluting compound were obtained as mono-Boc- (830 mg) protected compound.

Di-Boc: (650 mg)

tert-butyl 7-bromo-3- (tert-butoxycarbonylamino) -3,4-dihydro-1H-carbazole-9 (2H) -carboxylate

Mono-Boc: (830 mg)

tert-butyl 7-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamate

Step E

A solution of di-Boc protected compound (630 mg, 1.35 mmol) from this step in DMA (5 mL) was cooled to ice sox temperature and NaH (65 mg, 2.7 mmol) was added in part. The suspension was stirred at rt for 5 min and methyl iodine solution (380 mg, 2.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was dissolved in dichloromethane (250 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed and the crude product was purified on silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 50/50) to give the title compound (435 mg, 67% ).

Preparation Example 43

Step A

NaH (65 mg, 2.7 mmol) was partially added to a solution of monoprotected compound (750 mg, 2.05 mmmol) from Preparation Example 41 D in DMA (5 mL). The suspension was stirred at rt for 5 min and methyl iodine solution (380 mg, 2.7 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in dichloromethane (150 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed and the crude product was purified on a silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 50/50) to give the title compound (455 mg, 56%). .

Preparation Example 44

Step A

To a solution of 2,5-dibromopyridine (15 g, 64 mmol) was added NH ₂ NH ₂ H ₂ O (20 mL). The reaction mixture was refluxed for 2 days. The solvent was removed under reduced pressure, the crude product was dissolved in DCM (200 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed and the crude product was purified on a silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 50/50) to give the title compound (5.1 g, starting material). 59% based on recovery).

Step B

To a solution of the title compound (1.5 g, 6.7 mmol) from Step A above in ethanol (100 mL) was added a ketone derivative (1.6 g, 6.7 mmol) in ethanol (50 mL). The reaction mixture was stirred at room temperature for 5 hours. Solvent was removed and the title compound was obtained as a solid (3.1, quant.). The product was used in the next step without further purification.

Step C

A solution of the title compound (3.7 g, 8.9 mmol) from Step B above in diethylene glycol (12 mL) was sealed in a glass tube (20 mL) applicable to microwaves. The reaction mixture was then heated at 245 ° C. for 50 minutes using microwave. The reaction was carried out in three batches. The combined reaction mixture was dissolved in ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure, and the crude product was purified on a silica gel column using a Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 70/30). Purification gave the title compound as two regioisomers (1 g, 28.5%). The product was used in the next step without any further characterization.

Step D

To a stirred solution of compound (1.2 mg, 3.0 mmol) from Step C above in THF (50 mL) was added NH ₂ NH ₂ (5 mL). The reaction mixture was stirred for 2 days. The solid was filtered off. The filtrate was concentrated under reduced pressure and the crude product was dissolved in DCM (200 mL). The organic phase was washed with water and brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure, and the crude product (890 mg) was used in the next step without further purification.

Step E

To the crude product (0.89 g) from step D above in THF (20 mL) was added (Boc) ₂ O (2 g, 9.1 mmol) and triethylamine (5 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed and the crude product was purified on a silica gel column using a Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 60/40) to give the title compound (0.77 g, 24% , Overall yield from step 3).

Step F

NaH (180 mg, 7.5 mmol) was partially added to a solution of Boc-protected compound (700 mg, 1.9 mmmol) from Step E above in DMA (10 mL). The suspension was stirred at rt for 10 min and methyl iodine solution (1.2 g, 8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was dissolved in ethyl acetate (250 mL) and washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed and the crude product was purified on a silica gel column using the Biotage solera One purification system with EtOAc / n-heptane gradient (25/75 => 80/20) to give the title compound (435 mg, 67%). .

Preparation Example 45

Step A

To a solution of the title compound (0.25 g, 0.88 mmol) in DMA (5 mL) was added NaH (60 mg, 2.5 mmol) and the suspension was stirred for 5 minutes. Then a solution of 1-bromo-2-methoxyethane (245 mg, 1.77 mmol) was added. The reaction mixture was stirred at 50 ° C. for 3 hours in a sand bath. The reaction mixture was dissolved in EtOAc (150 mL), washed with water and brine and dried over Na ₂ SO ₄ . The product was purified on silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (20/80 => 80/20) to give the title compound (0.255 g, 85%).

Preparation Example 46

Step A

To a solution of the title compound (400 mg, 0.858 mmol) from Preparation Example 28 Step G in DMA (5 mL) was added NaH (31 mg, 1.29 mmol). The suspension was stirred at rt for 5 min and 1-bromo-2-methoxyethane (120 mg, 0.869 mmol) was added. The reaction mixture was heated at 50 < 0 > C overnight. The reaction mixture was cooled down, dissolved in ethyl acetate (150 mL), washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified on a silica gel column using Biotage Isolera One purification system with EtOAc / n-heptane gradient (1/99 => 20/80) to give the title compound (150 mg, 41%).

Step B

To a solution of mono-Boc derivative (80 mg, 0.188 mmol) from this step in DMA (2 mL) was added NaH (7 mg, 0.28 mmol). To this suspension was added methyl iodine (39 mg, 0.28 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was then dissolved in ethyl acetate (150 mL) and washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed and the crude product was purified on a silica gel column using the Biotage Isolera One purification system with EtOAc / n-heptane gradient (10/90 => 60/40) to give the title compound (70 mg, 85% ).

Preparation Example 47

Step A

To a solution of 1.8 M (33.0 mL, 59.3 mmol) of LDA solution in tetrahydrofuran (150 mL) at −75 ° C. was added commercially available 2-fluoropyridine (4.25 mL, 49.4 mmol). The mixture was stirred at the same temperature for 4 hours. To the resulting suspension, ethyl trifluoroacetate (7.08 mL, 59.3 mmol) is added and the internal temperature should not exceed -45 ° C. The reaction mixture was warmed up to room temperature. Nitromethane (5.31 mL, 99 mmol) was added and the reaction mixture was stirred at rt overnight. The slurry was diluted with ethyl acetate (100 mL) and 50 mL of 1.2 M HCl. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was suspended in dichloromethane and filtered to give the title compound as white crystals (6.14 g). The mother liquor was concentrated to dryness and purified by flash chromatography on ethyl acetate / n-heptane (20/80 to 35/65) to give additional material (4.45 g). Overall yield was 10.59 g (84%).

Step B

The title compound (4.45 g, 17.51 mmol) from step A above was dissolved in ethanol (50 mL) and stirred with hydrogen (0.141 g, 70.0 mmol) together with platinum (IV) oxide hydrate (0.398 g, 1.751 mmol). . After consumption of theoretical amount of hydrogen, the solution was filtered and the filtrate was refluxed overnight. Subsequently, the solvent was removed under reduced pressure. The title compound was obtained after chromatography purification using a gradient of dichloromethane / methanol (98/2 to 9/1) (1.2 g, 34%).

Step C

To a solution of the title compound (1.2 g, 5.88 mmol) from Step B above in tetrahydrofuran (15 mL) and pyridine (0.951 mL, 11.76 mmol) was added thionyl chloride (0.858 mL, 11.76 mmol) at 0 ° C. . The resulting mixture was stirred at rt for 24 h. The reaction mixture was poured into ice water. The mixture was neutralized with saturated sodium carbonate solution (pH 6). The aqueous layer was extracted with dichloromethane. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining pyridine was removed by addition of toluene and concentrated to dryness three times to give the title compound as a brown solid (1.13 g, 100%).

Step D

To a solution of 3-chloroperbenzoic acid (1.571 g, 9.11 mmol) in tetrahydrofuran (50 mL) was partially added the title compound (1.130 g, 6.07 mmol) from Step C above at 0 ° C. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness. The crude product was triturated with diethyl ether and then filtered (it was repeated several times). The mother liquor was concentrated to dryness and purified by flash chromatography using dichloromethane / methanol to give the title compound (1.37 g, 67%).

Step E

To a solution of the title compound (0.513 g, 1.430 mmol) from Step D above in dry toluene (30 mL) a solution of hexamethyldisilazane (0.6 mL, 2.86 mmol) in toluene and benzoyl bromide (0.421 mL, 3.58) in toluene mmol) was added simultaneously. The resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated to dryness. Purification of the residue by flash chromatography using ethyl acetate / n-heptane (15/85 to 35/65) gave the title compound as a white solid (0.190 g, 36%).

Step F

To a solution of the title compound (0.19 g, 0.515 mmol) from Step E above in methanol (10 ml) was added 1M aqueous solution of sodium hydroxide (1.544 mL, 1.544 mmol). The resulting solution was stirred at room temperature for 10 hours. Methanol was then removed under reduced pressure. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated to dryness to give the title compound as a white solid (0.122 g, 89%).

Step G

To a solution of the title compound (0.122 g, 0.460 mmol) from Step F above in dry tetrahydrofuran (10 ml) was added partly 60% sodium hydride (0.019 g, 0.483 mmol) at 0 ° C. The reaction mixture was stirred at rt for 20 min, then triisopropylsilyl chloride (0.099 mL, 0.460 mmol) was added. The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to dryness. The residue was diluted with ethyl acetate. Extraction was performed with saturated bicarbonate and brine. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography using ethyl acetate / n-heptane (15/85 to 40/60) to give the title compound as a white solid (0.188 g, 99%).

Preparation Example 48

Step A

A mixture of 0.6 mL of a hydrogen fluoride -70% solution in pyridine and dichloromethane (10 mL) was cooled to -10 ° C, and a commercially available solution of epoxide (2 g, 9.38 mmol) in dichloromethane (10 mL) was added dropwise. It was. The mixture was then stirred at rt for 4 h, diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed to give a residue, which was chromatographed on silica using ethyl acetate / n-heptane gradient (20/80-> 50/50) Purification by chromatography gave the title compound as a yellow oil (1.44 g, 66%).

Step B

The title compound (1.44 g, 6.17 mmol) from step A was dissolved in pyridine (6 mL) and the solution was cooled to 0 ° C. p-toluenesulfonyl chloride (1.29 g, 6.79 mmol) was added and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with dichloromethane (250 mL) and washed with water (50 mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed. Purification of the residue using a Biotage flash chromatography system (ethyl acetate / n-heptane: 20/80-> 50/50) gave the title compound as a yellow oil (2.2 g, 92%).

Step C

The title compound (2.2 g, 5.68 mmol) from Step B above was dissolved in N, N'-dimethylformamide (22 mL). Potassium phthalimide (1.052 g, 5.68 mmol) was added and the mixture was heated at 150 ° C. for 12 h. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 × 250 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and the solvent removed to give the title compound as a white solid (2.45 g), which was used directly in the next step.

Step D

The title compound (2.45 g) from Step C above was suspended in ethanolamine (6 mL). The mixture was heated at 60 ° C. for 2.5 h. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 250 mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed. Purification of the residue using a Biotage flash chromatography system (methanol / dichloromethane: 20/80-> 50/50) gave the title compound as a yellow oil (0.67 g, 46%, for step 3).

Preparation Example 49

Step A

To a solution of the title compound (1 g, 2.63 mmol) from Preparation Example 14, step D in dry tetrahydrofuran (25 ml) was partially added sodium hydride (0.111 g, 2.89 mmol, 60% in mineral oil) at 0 ° C. Was added. The mixture was stirred at rt for 30 min and then methyl iodine (0.491 ml, 7.89 mmol) was added. The solution was concentrated to dryness. Purification of the residue by flash chromatography in ethyl acetate / n-heptane (15% to 40%) gave the title compound as a white solid (0.98 g, 95%).

Preparation Example 50

Step A

1,2-dimethoxyethane (3 mL) was prepared for the title compound (0.021 g, 0.156 mmol) from Preparation Example 3, title compound (0.050 g, 0.141 mmol) from Preparation Example 1, Step D, tris (di Benzylideneacetone) dipalladium chloroform complex (0.013 g, 0.014 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos, 0.008 g, 0.014 mmol) and cesium carbonate (0.09 g , 0.283 mmol). The reaction mixture was degassed at room temperature under argon for 3 minutes and sonicated. The vial was then heated to 100 ° C. for 1 hour. The reaction mixture was extracted with ethyl acetate and brine. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification of the residue by flash chromatography using an ethyl acetate / n-heptane mixture afforded the title compound as a white solid (0.07 g, 12%).

Preparation Example 51

Step A

To a solution of commercially available 5-nitro-indole (3.4 g, 20.9 mmol) and 1-Boc-4-piperidone (6 g, 31.3 mmol) in methanol (50 mL) in methanol (10 mL) (28%) ) Sodium methoxide was added and the reaction mixture was heated at 80 ° C. for 2 days. The precipitated product was filtered off and dried to give the title compound as a yellow solid (5.1 g, 72%).

Step B

To a solution of the title compound (4 g, 11.6 mmol) from Step A above in tetrahydrofuran (150 mL) was partially added sodium hydride (0.42 g, 17.4 mmol). The dark red colored suspension was stirred at room temperature for 10 minutes. Triisopropylsilyl chloride (2.23 g, 11.6 mmol) was then added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and the solvent was removed. The residue was suspended in ethyl acetate (200 mL) and the starting material was removed by filtration. The filtrate was concentrated and the residue was purified on silica gel column (ethyl acetate / n-heptane (20/80)-> (60/40)) to give the title compound (2 g, 66%).

Step C

To a solution of the title compound (2 g, 4 mmol) from Step B above in ethyl acetate (150 mL) was added 10% Pd / C (0.5 g). The flask was evacuated and backfilled with hydrogen gas. The reaction mixture was then stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and dried to give crude product, which was purified by silica gel column using ethyl acetate / n-heptane (20/80-> 50/50) to give the title compound (1.31 g, 69%). .

Preparation Example 52

Step A

To a solution of the title compound (0.150 g, 0.534 mmol) from Preparation Example 33 Step F in dry tetrahydrofuran (volume: 10 ml) was added partly 60% sodium hydride (0.022 g, 0.560 mmol). After 30 minutes at room temperature d3-iomethane (0.040 ml, 0.640 mmol) was added dropwise. The resulting mixture was stirred at rt for 12 h. The reaction mixture was concentrated to dryness. Purification of the residue by flash chromatography in 15% to 50% of ethyl acetate / n-heptane gave the expected compound as a yellowish solid (0.95 g, 60%).

Preparation Example 53

Step A

To stirred ethanol (45 mL) was added ethyl carbrothoxy-4-piperidone (8.81 mL, 58.4 mmol) and 4-bromophenylhydrazine hydrochloride (13.06 g, 58.4 mmol). The resulting mixture was heated to 140 ° C. for 2 hours and then stirred overnight at room temperature. The slurry was filtered and rinsed with EtOH / water 1: 1. The cake was dried at 120 ° C. for 1 hour to give the title compound as an off white solid (12.75 g, 67%).

Step B

To a solution of the title compound (2.5 g, 7.74 mmol) from Step A in tetrahydrofuran (75 mL) was partially added 60% sodium hydride (0.311 g, 8.12 mmol) at 0 ° C. After 30 minutes at room temperature iodine methane (0.532 mL, 8.51 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness. Purification of the residue by flash chromatography in ethyl acetate / n-heptane (15-35%) gave the title compound as a white solid (2.52 g, 97%).

Preparation Example 54

Step A

To stirred ethanol (45 mL) was added ethyl carbrothoxy-4-piperidone (4.41 mL, 29.2 mmol) and 3-bromophenylhydrazine hydrochloride (6.53 g, 29.2 mmol). The resulting mixture was heated to 140 ° C. for 12 h and then stirred at rt overnight. The slurry was filtered and rinsed with EtOH / water 1: 1 to afford the title product as a mixture of two isomers (2.98 g, 32%).

Step B

To a solution of the title compound (2.979 g, 9.22 mmol) from Step A in dichloromethane (150 mL) was added DMAP (0.056 g, 0.461 mmol) followed by Boc ₂ O (2.68 mL, 11.52 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. Purification of the residue by flash chromatography (2 ×) using ethyl acetate / n-heptane (10% to 20%) gave the title compound as a white solid (1.82 g, 47%).

Step C

To a suspension of the title compound (1 g, 2.362 mmol) from Step B in methanol (25 mL) was added potassium carbonate (0.979 g, 7.09 mmol). The resulting mixture was refluxed for 3 hours. The reaction mixture was concentrated to dryness. The residue was extracted with ethyl acetate and brine. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography on an ethyl acetate / n-heptane mixture to give the title compound as a white solid (0.746 g, 98%).

Step D

To a solution of the title compound (0.746 g, 2.308 mmol) from Step C in dry tetrahydrofuran (25 mL) was partially added 60% (0.101 g, 2.424 mmol) of sodium hydride at 0 ° C. After stirring 30 minutes at room temperature, iodine methane (0.166 mL, 2.65 mmol) was added dropwise. The resulting mixture was stirred at rt for 4 h. The resulting mixture was concentrated to dryness and the crude product was purified by flash chromatography on an ethyl acetate / n-heptane mixture to afford the desired compound as a white solid (0.657 g, 84%).

Preparation Example 55

Step A

Anhydrous ethanol (volume: 20 ml) in a mixture of (4-bromophenyl) hydrazine, HCl (1 g, 4.47 mmol) and dihydro-2H-thiopyran-4 (3H) -one (0.520 g, 4.47 mmol) Was added. The resulting slurry was stirred at room temperature for 2 hours. The resulting slurry was concentrated to dryness to a corresponding hydrazone. The solid was partitioned into microwave vials and suspended in ethanol (volume: 15 ml). The resulting slurry was heated to 125 ° C. for 25 minutes by microwave. The reaction mixture was dropped into water with vigorous stirring. The resulting beige suspension was filtered and then dried overnight in air. The crude product was crystallized from ethanol. The product remaining in the mother liquor was recovered by flash chromatography in DCM / MeOH 2% to 5%. This resulted in the title compound as a white solid (4.16 g, 87%).

Step B

To a solution of the title compound (0.809 g, 3.02 mmol) from Step A in dry tetrahydrofuran (volume: 50 ml) was added 60% sodium hydride (0.139 g, 3.32 mmol) at 0 ° C. The resulting mixture was stirred at rt for 30 min, then iodine methane (0.283 ml, 4.53 mmol) was added. The resulting solution was stirred at room temperature for 12 hours. The mixture was concentrated to dryness and the crude product was purified by flash chromatography on ethyl acetate / n-heptane 10-30% to give the title compound as a yellow solid (0.811 g, 95%).

Step C

To a solution of the title compound (0.5 g, 1.772 mmol) from Step B in ethyl acetate (volume: 4 ml) was added dropwise peracetic acid (0.706 ml, 3.72 mmol) at 0 ° C. The light yellow slurry was stirred for 4 hours at room temperature. The reaction mixture was concentrated to dryness. The crude product was purified by flash chromatography at 40% -65% ethyl acetate / n-heptane to give the expected compound as a yellowish solid (0.320 g, 57%).

Preparation Example 56

Step A

Anhydrous ethanol (volume: 20 ml) in a mixture of (3-bromophenyl) hydrazine, HCl (1 g, 4.47 mmol) and dihydro-2H-thiopyran-4 (3H) -one (0.520 g, 4.47 mmol) Was added. The resulting slurry was stirred at room temperature for 2 hours. The resulting slurry was concentrated to dryness to a corresponding hydrazone. The solid was partitioned into microwave vials and suspended in ethanol (volume: 15 ml). The resulting slurry was heated to 125 ° C. for 25 minutes by microwave. The mixture was dropped into water with vigorous stirring. Extraction in DCM was performed with HCl 1M and water. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography in DCM / MeOH 95: 5 to give the title compound as a beige solid (0.328 g, 27%).

Step B

To a solution of the title compound (0.298 g, 1.111 mmol) from Step A in dry tetrahydrofuran (volume: 20 ml) was added 60% sodium hydride (0.0488 g, 1.167 mmol) at 0 ° C. The resulting mixture was stirred at rt for 30 min, then iodine methane (0.076 ml, 1.222 mmol) was added. The resulting solution was stirred at room temperature for 12 hours. The mixture was concentrated to dryness and the crude product was purified by flash chromatography at 10-30% ethyl acetate / n-heptane to give the title compound as a white solid (0.310 g, 99%).

Step C

To a solution of the title compound (0.3 g, 1.063 mmol) from step B in ethyl acetate (ratio: 1.000, volume: 20 ml) peracetic acid (0.403 ml, 2.126 mmol) in ethyl acetate (ratio: 1.000, volume: 20.00 ml) ) Was added dropwise at room temperature. The resulting mixture was stirred at rt for 12 h. The reaction mixture was extracted with saturated solution of water and Na ₂ CO ₃ . The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification of the residue by flash chromatography in 40% -65% ethyl acetate / n-heptane gave the expected compound as a white solid (0.160 g, 48%).

Preparation Example 57

Step A

Meta-chloroperoxybenzoic acid (mCPBA; 9.32 g, 41.6 mmol) in an ice-cooled solution of 4- (methylthio) butan-1-ol (2.5 g, 20.80 mmol) in dry dichloromethane (volume: 250 ml) Was added in part. The resulting mixture was stirred at rt for 20 h. The solution was concentrated to dryness. The residue was dissolved in a mixture of diethyl ether and water. Benzoic acid was extracted with diethyl ether. The water layer was concentrated to dryness. The residue was diluted with DCM and the concentrated solution was loaded into the samplelets. The crude product was purified by flash chromatography in DCM / MeOH 3-10% to afford the title compound as a colorless oil (2.95 g, 93%).

Step B

To a mixture of the title compound (2.95 g, 19.38 mmol), triphenylphosphine (7.62 g, 29.1 mmol) and imidazole (1.979 g, 29.1 mmol) from Step A in dichloromethane (volume: 250 ml), iodine ( 7.38 g, 29.1 mmol) was added dropwise. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated in half, then water was added. The slurry was filtered and extracted with a solution of Na ₂ SO ₃ . The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification of the residue by flash chromatography in ethyl acetate / n-heptane 40% to 60% gave the expected compound as a white solid (1.2 g, 24%).

Preparation Example 58

The following compounds were prepared following the procedure described in Preparation Example 54, except that the propyl-derivatives shown in the following scheme were used.

Yield: 72%

Preparation Example 59

Step A

OXONE (52.9 g, 86 mmol) was added to a mixture of dihydro-2H-thiopyran-4 (3H) -one (5 g, 43.0 mmol) in acetone (volume: 100 ml). The resulting mixture was stirred vigorously for 12 hours at room temperature. The slurry was filtered and the solid was rinsed with acetone. The organic layer was concentrated to dryness to afford the title compound as a white solid (5.83 g, 91%).

Step B

To a mixture of the title compound (2 g, 13.50 mmol) from Step A in methanol (volume: 50 ml) was added sodium borohydride (0.511 g, 13.50 mmol) at 0 ° C. The resulting mixture was stirred at rt for 1 h. The solution was concentrated to dryness. Purification of the residue by flash chromatography in DCM / MeOH 0% to 5% gave the title compound as a white solid (1.74 g, 86%).

Step C

Iodine (2.53) in a mixture of the title compound (1.0 g, 6.66 mmol), triphenylphosphine (2.62 g, 9.99 mmol) and imidazole (0.680 g, 9.99 mmol) from step B in dichloromethane (volume: 50 ml). g, 9.99 mmol) was added dropwise. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was filtered, then concentrated to dryness. Purification of the residue by flash chromatography in 40% to 75% ethyl acetate / n-heptane gave the expected compound as a white solid (0.684 g, 39%).

Preparation Example 60

Step A

The oven dried shrink flask was evacuated and backfilled with argon gas. This process was repeated 3-4 times. Dioxane (3 mL) was added by syringe at room temperature and degassed by bubbling argon through the mixture. Then 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos, 0.054 g, 0.112 mmol) and palladium (II) acetate (0.009 g, 0.037 mmol) were added together. The mixture was heated at 110 ° C. for 1 minute. The reaction mixture turned into a solution of vivid red color. The title compound (0.050 g, 0.375 mmol) from Preparation Example 3, then commercially available 6-bromo-1- (triisopropylsilyl) -1H-pyrrolo [3,2-b] pyridine (0.132 g , 0.375 mmol) and sodium tert butoxide (0.12 g, 1.25 mmol) were added together under argon atmosphere. The reaction mixture was heated at 110 < 0 > C for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was washed with water, brine and dried over Na ₂ S0 ₄ . The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate to give the title compound (0.045 g, 30%).

Preparation Examples 61-140

Preparation Example 142

Step A

To a solution of the title compound (0.120 g, 0.2 mmol) from Preparation Example 75 in THF (1 mL) was added tetra-butyl ammonium (0.052 g, 0.2 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was then concentrated. The crude product was purified using a silica gel column (1: 1, EtOAc: heptanes) to afford the title compound (0.08 g, 94%).

Step B

To a solution of the title compound (0.08 g, 0.187 mmol) from Step A in THF (3 mL) was added sodium hydride (0.007 g, 0.28 mmol), followed by methyl iodine (0.026 g, 0.187 mmol), resulting in The resulting reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with water and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was purified on silica gel column (EtOAc: heptane; 40:60) to afford the title compound (0.025 g, 30%).

Preparation Examples 143 and 144

Step A

To a solution of the title compound (0.3 g, 0.323 mmol) from Preparation Example 69 in THF (3 mL) was added tetrabutylammonium fluoride (0.08 g, 0.323 mmol) and the reaction mixture was stirred at rt for 1 h. Solvent was removed and the residue was purified on silica gel column (EtOAc vs. heptane; 20-100%) to afford the title compound (0.127 g, 64%).

Step B

To a solution of the title compound (0.05 g, 0.081 mmol) from Step A above in THF (5 mL) was added sodium hydride (0.004 g, 0.16 mmol) followed by methyl iodine (0.022 g, 0.15 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then quenched with a drop of methanol and the solvent was removed. The crude mixture was purified on a silica gel column to give the dimethylated title compound (0.021 g) and trimethylated title compound (0.010 g).

Dimethylated compound 143,

Trimethylated compound 144,

Preparation Example 145

Step A

Tert-butanol (2 mL) was degassed by sonication for 1 minute while passing the argon stream through the solution. Palladium (II) acetate (0.003 g, 0.0127 mmol) and 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos, 0.018 g) in degassed tert-butanol (1 mL) , 0.038 mmol) was added. This mixture was heated in a sand-bath at ˜100 ° C. for 1 minute to produce a catalyst. Then commercially available 3,4-difluoro aniline (0.019 g, 0.15 mmol) in tert-butanol (1 mL) degassed in a light red catalyst solution and the title compound (0.045 g) from Preparation Example 1, step D , 0.127 mmol) was added. After addition of potassium carbonate (0.039 g, 0.28 mmol), the mixture was heated in ˜110 ° C. for 3 h in a sand-bath. The mixture was diluted with ethyl acetate (30 mL), water (10 mL) and brine (10 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified by chromatography on silica using ethyl acetate / n-heptane (20/80) to give the title compound as an off-white solid (0.045 g, 87%).

Preparation Examples 146-256

The following compounds were prepared following the Pd-coupling procedure described in Preparation Example 145, except for the use of bromo-derivatives and amines shown in the table below.

Preparation Example 258

Step A

To a solution of the title compound (0.056 g, 0.091 mmol) from Preparation Example 66 in THF (1 mL) was added tetrabutylammonium fluoride (0.024 g, 0.091 mmol) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated and the residue was purified on silica gel column (25% -100% EtOAc / heptanes: isocratic mixture) to give the title compound (0.026 g, 63%).

Preparation Example 259

Step A

The title compound (0.049 g, 0.08 mmol) from Preparation Example 150 was dissolved in acetonitrile (1 mL) and dichloromethane (1 mL) and tetrabutylammonium fluoride (0.1 mL, 0.1 mmol, 1.25 in tetrahydrofuran). eq.1 per TIPS-group). The mixture was stirred at rt for 1 h and the solvent was removed. The residue was purified by chromatography on silica using dichloromethane / acetone (95/5) to give the title compound as pale yellow glass (0.029 g, 82%).

Preparation Example 260

Step A

To a solution of the title compound (0.150 g, 0.3 mmol) from Preparation Example 82 in THF (5 mL) was added polymer supported fluoride (Aldrich 387789) (0.4 g). The mixture was stirred overnight, filtered and the solvent was evaporated. The solvent was filtered off and concentrated and the residue was purified on a silica gel column (methanol to dichloromethane; 5 to 15%) to give the title compound (0.075 g, 73%).

Preparation Examples 261-330

The following compounds were prepared following a procedure similar to that described in Preparation Examples 258 (A), 259 (B), 260 (C), except that the compounds from the Preparation Examples shown in the following table were used.

Preparation Example 331

Preparation Example 332

Step A

To a solution of the title compound (0.127 g, 0.330 mmol) from Preparation Example 227 in dry ethanol (volume: 10 ml) was added sodium hydroxide (0.132 g, 3.30 mmol). The resulting mixture was heated to 180 ° C. for 20 minutes by microwave. The solution was concentrated to dryness. The product was extracted with ethyl acetate and brine. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification of the residue by flash chromatography in DCM / MeOH gave the title compound as a reddish solid (0.070 g, 68%).

Preparation Examples 333-335

The following compounds were prepared following the deprotection procedure described in Preparation Example 332, except that the carbamate-derivatives shown in the table below were used.

Example 1

Step A

The title compound (0.048 g, 0.125 mmol) from Preparation Example 1 was dissolved / suspended in acetonitrile (1 mL) and treated with a 1 M solution of tetrabutylammonium fluoride (0.15 mL, 0.15 mmol) in tetrahydrofuran. It was. The mixture was stirred at rt for 1 h and the solvent was removed. The residue was purified by PREP-TLC using ethyl acetate to give the free base as an orange oil. This material was treated with a 1 M aqueous solution of hydrogen chloride (3 mL). The solvent was removed using a freeze dryer to afford the title compound as a pale yellow solid (0.028 g, 73%).

Examples 2 to 23

The following compounds were prepared following a similar procedure as described in Example 1, except that the compounds from the preparation examples shown in the following table were used. For the preparation examples without TIPS-protecting groups, only aqueous hydrogen chloride treatment was performed. For Examples 19-23 polymer supported fluorine was used for the degradation of TIPS-protecting groups.

All example compounds below were obtained as their HCl-salts unless otherwise indicated.

Example 24

Step A

The title compound (0.03 g, 0.07 mmol) from Preparation Example 259 was dissolved in dichloromethane (1 mL) and treated with a 2M solution of hydrogen chloride (1 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (5 mL) and then dried under reduced pressure to afford the title compound as an off white solid (0.021 g, 75%).

Examples 25-203

The following compounds were prepared following a similar procedure as described in Example 24, except that the compounds from the preparation examples shown in the following table were used. If no precipitate formed, the solvent was removed and the residue was dissolved in water (5 mL). The aqueous solution was evaporated using a freeze dryer to afford the title compounds. All example compounds below were obtained as their HCl-salts unless otherwise indicated.

Example 204

Step A

The title compound (0.032 g, 0.093 mmol) from Preparation Example 203 was dissolved in methanol (2 mL) and concentrated aqueous hydrogen chloride solution was added. The clear solution was frozen in liquid nitrogen and the solvent was evaporated using a freeze drier to give the title compound as an off white solid (0.029 g, 81%).

Example 205

The same procedure as described for Example 204 was applied except that the title compound from Preparation Example 204 was used.

Yield: 76%

Example 206

Step A

To a solution of the title compound (0.070 g, 0.223 mmol) from Preparation Example 332 in methanol (volume: 4 ml) was added a formaldehyde solution (0.020 ml, 0.246 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.0568 g, 0.268 mmol) was partially added. The resulting mixture was stirred at rt for 12 h. 1 mL of HCl 1.2 M in water was added. After 5 minutes stirring at room temperature, the solution was poured into a mixture of water, saturated Na ₂ CO ₃ and brine. Extracted three times with ethyl acetate. The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography in DCM / MeOH 98: 2 to 90:10. The product was dissolved in DCM and HCl and ether was added slowly to form the corresponding HCl salt. The solvent was concentrated to dryness and the solids dried under vacuum to afford the expected compound as a purple solid (0.028 g, 34%).

Example 207

Step A

Tetrahydrofuran (ratio :) in a mixture of the title compound (0.036 g, 0.107 mmol) from Preparation Example 334, the title compound (0.0281 mg, 0.107 mmol) and potassium carbonate (0.0297 mg, 0.215 mmol) from Preparation Example 54. 1.000, volume: 2 ml) was added followed by acetonitrile (ratio: 1.000, volume: 2.000 ml). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography in DCM / MeOH 0% to 10%. The product was dissolved in DCM and HCl and ether was added. The slurry was concentrated to dryness. The residue was dissolved in a few drops of MeOH and ethyl acetate was added to induce precipitation. The slurry was concentrated to dryness to afford the expected compound as a beige solid (0.020 g, 37%).

Examples 208 to 210

The title compound was prepared following the procedure described in Example 207 using the iodine-derivatives shown in the table below.

Examples 211-218:

When treating the title compounds from the preparation examples with an iodine-derivative as described in Example 207, the desired examples shown in the table below will be obtained.

Examples 219-222:

When treating the title compounds from the preparation examples with vinylsulfone derivatives according to WO2008 / 150799, the desired title compounds shown in the table below will be obtained.

Compounds of the present invention having one or more optically active carbons include racemic and racemic mixtures, diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, tautomers, atropisomers and morphomers ( rotamer) and all isomeric forms are included in the present invention. Compounds described herein containing olefinic double bonds include both E and Z geometric isomers. The invention also includes all salt forms, polymorphs, hydrates and solvates. All of the foregoing compounds are included within the scope of the present invention.

Measurement of Aβ1-42 Aggregation Inhibition

The ability of the example compounds of the present invention to inhibit aggregation of Ab1-42 peptides was measured using Thioflavin T spectrofluorescence analysis (ThT-assay) described below.

Preparation of Aβ Peptide Film

Aβ1-42 lyophilized powder (Bachem) was reconstituted at 1 mM in hexafluoroisopropanol (HFIP). Peptide solutions were sonicated for 15 minutes at room temperature, stirred overnight, and aliquots were placed in non-siliconized microcentrifuge tubes. HFIP was then evaporated under an argon stream. The resulting peptide film was dried under vacuum for 10 minutes and stored at −80 ° C. until tightly sealed and used.

Inhibition measurement of Aβ1-42 aggregation

To analyze the small molecule-mediated inhibition of Aβ1-42 aggregation, small molecules from the examples were dissolved in anhydrous dimethylsulfoxide (DMSO, Sigma-Aldrich) before each experiment to reach a concentration of 7.4 mM. . The A [beta] 1-42 peptide film was dissolved in DMSO to reach 400 [mu] M. The assay solution in PBS was made in a non-silicated incubation tube to reach the following concentrations: 330 μΜ žž, molecules, 33 μΜ Aβ1-42, 10 μM thioflavin T (ThT), and 12.8% DMSO. Thus, the final molar ratio of small molecules to A? 1-42 was 10: 1. The maximum RFU was measured by making a positive control without a small molecule. A negative control without A [beta] 1-42 was made for each small molecule. In all assays, 3-aminopyrazole trimer (Rrimpecki et al. Synthesis 2003, 1815) was tested as a reference compound to confirm reproducibility between independent experiments. The solution was then incubated at 37 ° C. for 24 hours, and fluorescence fluorescence units (RFU) were read in six replicates in a black 384-well assay plate (Perkin-Elmer) on a Perkin-Elmer FluoroCount spectrofluorometer. . The inhibition of aggregation is expressed as mean inhibition% or ± 1 standard deviation (SD) according to the following formula:

The compounds of the following examples were measured.

Table 10:

Inhibition of Aβ1-42 aggregation of Aβ1-42 fibers preformed by molecules. Results are expressed as mean ± standard deviation of two independent experiments.

Inhibition of Aβ1-42 aggregation of preformed Aβ1-42 fibers could not be measured for Examples 5 and 7 due to very strong autofluorescence.

Example 211: Effect of ACI-636 on Plaque Formation in hAPPSL Transgenic Mice

The purpose of this study was to evaluate the properties of ACI636 regarding the inhibition of plaque formation and the dissolution of plaque present.

211.1 Method

Transgenic (Tg) mice overexpressing human amyloid protein (hAPP) are a suitable model for studying the effects of drugs on amyloid production, sequestration, and deposition. For this study, mice overexpressing the 751 amino acid form of hAPP with London (V717I) and Swedish (KM670 / 671NL) mutations under the control of the mouse Thy-1 promoter (hAPPSL mice) were used. hAPPSL mice showed an age-dependent increase in β-amyloid peptide (Aβ) and progressed plaques consisting of amyloid deposition at early age (starting at 4-6 months). The severity of brain pathology is associated with increasing age and behavioral deficits. Starting at the age of 13 to 14 months, female hAPPSL Tg mice were treated once daily by gavage with 10 mg / kg of ACI-636 as described in the table below.

At the end of the treatment period, animals were sacrificed and blood (plasma) and brain collected. The effect of ACI-636 on Aβ levels (Aβ38, Aβ40, Aβ42) in four different brain homogenate fractions (TBS, Triton X-100, SDS and FA) was measured by Aβ-kit from Mesoscale Discovery. In addition, amyloid deposition was measured immunohistochemically in brain samples detected by 6E10 antibodies. Aβ levels were evaluated as compared to peptide standards as pg / mg species brain weight.

211.2 results

Overall, animals receiving ACI-636 for 14 days tended to increase soluble Αβ levels (TBS and Triton X-100 fractions) and decrease insoluble β levels (SDS and FA fractions) compared to PBS treated animals. Showed. The effect of treating animals with ACI-636 relative to vehicle is referred to as "treatment induced difference". Quantification of cortex (a and b) and hippocampus (c and d) 6E10 immunofluorescence is shown in FIG. 1. The effect of treatment of female mice treated for 14 days affects the number of plaques and the total area (Note: minimum target size> 150 μm ² ). Abbreviation: vehicle (A); ACI-636 10 mg / kg / day (B).

In contrast to vehicle, treatment with ACI636 consistently reduced plaque load in female Tg mice 14 days after treatment.

211.3 Conclusion

Animals receiving ACI-636 for 14 days showed a tendency for an increase in soluble Αβ levels (TBS and Triton X-100 fractions) and a decrease in non soluble Αβ levels (SDS and FA fractions) compared to vehicle treated animals. When administered for 14 days, ACI636 selectively reduced amyloid load in female hAPP751SL transgenic mice, both in extracellular plaque load and total amyloid load, including intracellular amyloid. The effect was better in the cortex than in the hippocampus.

Example 212 Effect of ACI-636 on the Behavior of APPV171I Transgenic Mice

The purpose of this study was to measure the efficacy of ACI-636 in a mouse model of Alzheimer's disease. The impact of memory therapy was assessed by the spatial cognitive test (SRT).

212.1 Method

212.1.1 Spatial Cognitive Test (SRT)

The new object recognition test (ORT) is an in vivo test to investigate the effects of test substances on memory in rodents (mouse, rats). This test was introduced to measure non-spatial memory by their ability to recognize new objects in unfamiliar environments in rodents (Ennaceur, A. and Delacour, J. Behav. Brain Res. 1988, 31, 47-59 ). The test provides information about short-term or long-term memory, exploratory or provocative effects of the test substance, and search behavior associated with attention. In the learning phase of the test, the animal faces two identical objects located in an open field to get used to the objects. On memory, the animal is exposed to two different objects located in an open field: one is similar to that used in learning, and one is a new object. In memory, the time spent exploring each object is measured. The search for an object is defined as the time spent when the head is within two centimeters of the object. Non-killing animals will spend more time exploring new objects than are familiar objects. To increase the challenge for animals, the ORT test was modified to include a spatial memory element (spatial cognition test (SRT)) using two identical objects. In SRT-setting, one object remains in the retention phase at the same location as on the previous learning, while the other object is located at a different location. A total of 24 female APPV171I transgenic mice (10 months old) were treated by gavage once a day (12 mice treated with ACI-636; 10 mg / kg) and by PBS (12 mouse treatment). After 21 days of treatment, two different objects (one cube lego (2.9 cm x 5.8 cm) and a black glass bottle (5.3 cm x 5.3 cm) in a gray polypropylene maze (circular development field, 40 cm in diameter, 32.4 cm in height) SRT-test was performed using the following experiments.

1 day:

Desensitization of the instrument for each animal without objects (10 minutes).

2 days:

Study session: Two identical objects (cube lego or black glass bottles) were presented on one side of the maze (10 minutes).

Memory test (3 hours after learning): One of the same objects was presented on the opposite side of the maze (10 minutes).

212.2 results

In Figures 2A and 2B, APPV171I transgenic mice treated with PBS and ACI-636 were distributed. Statistical analysis of cognitive index (RI) for duration and frequency (Figures 2A and 2B) using a paired t-test assay showed a significant difference between PBS and ACI-636 treated APPV171I transgenic mice. (p <0.05).

212.3 Conclusion

In the spatial cognitive test (SRT), APPV171I transgenic mice treated with ACI-636 spent more time searching for moved objects than familiar objects compared to APPV171I transgenic mice treated with vehicle (PBS), which Cognitive tests demonstrate the effect of ACI-636 on short-term memory.

Example 213 Preparation of Compounds 213a and 213b (enantiomer of Compound 26): Chiral Separation

213.1 Purpose and design of the study

The purpose of this study is to isolate and characterize the two enantiomers of Compound 26.

213.2 Method

Compound 26 (N ^2- (3,4-difluorophenyl) -N ^{6 , 9} -dimethyl-6,7,8,9-tetrahydro-5H-pyrido [2, by HPLC using chiral phase] 3-b] Isolation of Boc-Protected Precursor of Indole-2,6-diamine Hydrogen Chloride; Racemate)

Enantiomers of Boc-protected precursors of compound 26 (0.110 g, racemate) were separated. In total, 0.040 g of the initial enantiomer and 0.033 g of the final enantiomer were obtained. Each enantiomer contained less than 1% of other enantiomers as determined by chiral HPLC.

Chiral HPLC conditions

* Chiralpak IA, 4.6 x 250 mm, 5 μm

Mobile phase: n-heptane / iso-propanol (95: 5)

Flow rate: 1 mL / min

Wavelength: 254 nm

FIG. 3 shows the separation of Boc-protected precursors of Compound 26 by chiral HPLC.

R _t (initial enantiomer): 22.7 min

R _t (terminal enantiomer): 31.6 minutes

4 shows the initial enantiomers after separation, and FIG. 5 shows the late enantiomers after separation.

213.3 Preparation of Final Compounds

All reagents and solvents were obtained from commercially available and used without further purification. Proton ( ¹ H) spectra were recorded on a 400 MHz NMR spectrometer in deuterated solvent. Mass spectra (MS) were recorded on a Finnigan MAT TSQ 7000 spectrometer. Optical rotation of the enantiomers was recorded with a JASCO polarimeter at 25 ° C. using a wavelength of 589 nm in methanol.

213.3.1 Preparation of Compound 213a

After HPLC separation the initial enantiomer (0.039 g, 0.088 mmol) was dissolved in dichloromethane (1.2 mL) and treated with a 2 M solution of hydrogen chloride (1.2 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (5 mL) and dried under reduced pressure to afford the title compound as an off white solid (0.029 g, 88%).

213.3.2 Preparation of Compound 213b

After HPLC separation, the late enantiomer (0.022 g, 0.05 mmol) was dissolved in dichloromethane (1 mL) and treated with a 2 M solution of hydrogen chloride (1 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (5 mL) and dried under reduced pressure to afford the title compound as an off white solid (0.013 g, 71%).

213.4 Conclusion

The racemic Boc-protected precursor of compound 26 successfully separated into its two enantiomers. Decomposition of the protecting group of the initial eluting enantiomer gave (+)-enantiomer compound 213a, and the (-)-enantiomer compound 213b as terminal eluting enantiomer.

Preparation Example 336 tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indole- by separation of diastereomers Preparation of single enantiomer of 6-yl) methyl) carbamate

336.1 Purpose and design of the study

The goal of this study was to obtain tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indole- via separation of diastereomers. To develop a process for preparing single enantiomers of 6-yl) methyl) carbamate.

342.2 method

336.2.1 Principle of enantiomeric separation

The racemic compound was optionally reacted with the active reagent L (amino acid-derivative) to give a mixture of diastereomers (RL and SL), which were separated by chromatography. The chiral reagents were subsequently removed by acid treatment to produce building blocks rich in enantiomers.

Enantiomer-rich (tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-6-yl) -methyl) Synthetic Schemes for the Preparation of Carbamate

Preparation of chiral auxiliary (S) -2-((2,4-dinitrophenyl) amino) -3-phenylpropionic acid

Triethylamine (7.86 ml, 56.4 mmol) was added to a mixture of L-phenylalanine (8.88 g, 53.7 mmol) and 1-fluoro-2,4-dinitrobenzene (3.24 ml, 26.9 mmol). The resulting mixture was heated to 100 ° C. for 4 minutes using Biotage Initiator microwaves. The solid was diluted with MeOH and the slurry was dropped in diluted water. Dichloromethane was added to the slurry and the organic phase was separated. The organic phase was further extracted with 1.2 M hydrogen chloride solution and brine. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was diluted with dichloromethane and the slurry was filtered. The precipitate was then washed with a small amount of dichloromethane. The combined filtrates were evaporated and the residue was purified by flash chromatography using dichloromethane / methanol gradient (0% to 5%) to afford the title compound.

Step A

Racemic tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-6-yl) in 20 mL of dichloromethane To a solution of methyl) carbamate (0.9 g, 2.28 mmol) was added 11.34 ml (22.8 mmol) of a 2 M solution of hydrogen chloride in diethyl ether and the reaction mixture was stirred at rt for 12 h. After dilution with dichloromethane, the solution was basified with aqueous sodium hydroxide solution until pH 13-14. The organic phase was separated and the aqueous phase extracted with dichloromethane (4 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed to afford the title compound as a brownish oil.

Step B

The crude title compound (2.28 mmol) from step A above was dissolved in N, N′-dimethylformamide (14 mL). (S) -2-((2,4-dinitrophenyl) amino) -3-phenylpropionic acid (0.944 g, 2.85 mmol) followed by HBTU (1.08 g, 2.85 mmol) and triethyl amine (0.68 mL, 5.01 mmol ) Was added. The solution was stirred at rt for 12 h. The reaction mixture was diluted with dichloromethane (500 mL) and washed with water (100 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (4 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed to afford the crude product as an orange solid.

Step C

Diastereoisomeric Separation by Flash Chromatography on Silica

The mixture of diastereomers from Step B was separated using a Biotage Isolera One flash chromatography system to yield 0.64 g of the initial diastereomer and 0.7 g of the terminal diastereomer.

The following conditions were used:

Cartridge loading : 250 mg-500 mg mixture applied to 100 g HP-Sil SNAP cartridge

Solvent Gradient : EtOAc / n-heptane: 30-50%

Chromatographic separation of a mixture of diastereomers on silica-gel (flow rate: 50 ml / min) using ethyl acetate / n-heptane gradient (30/70-> 60/40) was carried out.

¹ H-NMR data of the initial diastereomers (aromatic regions only, impurities are present in regions 7.1-7.3 ppm) are shown in FIG. 11.

¹ H-NMR data of the terminal diastereomers (aromatic regions only, impurities are present in regions 7.1-7.3 ppm) are shown in FIG. 12.

Step D

The terminal diastereomer (0.7 g, 1.15 mmol) from Step C above was dissolved in 18 mL of glacial acetic acid and then 18 mL of concentrated hydrochloric acid (36-38%) was added. The mixture was heated at 120 ° C. for 5 days in a sand bath. The reaction mixture was cooled at room temperature, then diluted with 400 mL dichloromethane and basified with 1 M aqueous sodium hydroxide solution until pH 13-14. The organic phase was separated and the aqueous phase extracted with dichloromethane (4 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed to give the crude product as a brownish oil.

Step E

The crude compound (1.15 mmol) from step D above was dissolved in tetrahydrofuran (16 mL) and treated with triethylamine (0.176 mL) and di-tert-butyl dicarbonate (0.95 g, 12.4 mmol). The mixture was left at rt overnight. The solvent was removed and the residue was purified using a Biotage purification system (EtOAc / n-heptane: 10-40%) to give a Boc-protected tricyclic building block derived from the terminal diastereomers as an off-white solid ( 0.22 g, 24% for step 4).

The initial diastereomers were treated as described above (steps D and E) to obtain the corresponding initial enantiomer tricyclic building blocks.

Preparation Example 337 tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indole by separation of salts of diastereomers Preparation of single enantiomer of -6-yl) methyl) carbamate

337.1 Objectives and design of the study

The goal of this study was to obtain a racemic tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indole via diastereomeric salts. To develop a separation method of -6-yl) methyl) carbamate.

337.2 Method

337.2.1 Principles of Enantiomeric Separation

The salt mixture as the free base of the racemic compound, optionally activated acid and reacting the diastereomeric _{^{(R + L 1 - + S}} + L 1 -) was obtained. Crystallization of the diastereomeric salts with the appropriate solvent and removal of the chiral auxiliaries resulted in individual enantiomers.

individual enantiomers of tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-6-yl) methyl) carbamate Schemes for the preparation of

Step A

Racemic tert-butyl- (2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-6-yl) in 300 mL of dichloromethane A solution of methyl) carbamate (12.48 g, 31.87 mmol) was cooled to 0 ° C. Then a 150 ml (300 mmol) solution of 2 M solution of hydrogen chloride in diethyl ether was added at 0 ° C. After the addition was complete, the ice-bath was removed and the reaction mixture was stirred at rt for 16 h. The precipitate was collected by filtration, washed with diethyl ether (100 mL) and air-dried to give the di-hydrochloride salt as an off-white solid (11.5 g, quant.). Sodium hydroxide (1.27 g, 32 mmol of NaOH in 22 mL of water) in a 250 mL flask equipped with a magnetic stirrer containing di-hydrochloride salt (3.65 g, 10 mmol) as a suspension in water (37 mL) An aqueous solution of was added (addition time 1 minute). The flask containing sodium hydroxide solution was then rinsed with additional water (2 x 3 mL). The resulting white suspension was stirred vigorously for 5 minutes before adding dichloromethane (65 mL). The resulting mixture was stirred vigorously for 5 minutes. The organic phase was recovered and the aqueous phase extracted with 3 x 65 mL dichloromethane. The combined organic phases were dried over MgSO ₄ and evaporated to dryness in vacuo at room temperature to give 2.63 g (90%) of the title compound as a yellow solid.

Enantiomeric Separation via Diastereomeric Salts:

Step B (enantiomer B obtained by reaction with (S)-(+)-mandelic acid, R _t = 26.1 min)

(S)-dissolved in methanol (50 mL) in a 250 mL flask equipped with a magnetic stirrer containing the title compound (5.46 g, 18.6 mmol) from step A dissolved in methanol (30 mL) at 35 ° C. (+)-Mandelic acid (1.35 g, 8.9 mmol) was added. The resulting mixture was stirred at 35 ° C. (internal temperature) for 24 hours and then filtered through a sintered glass funnel. The mother liquor was separated and the resulting white solid was washed with methanol at room temperature (3 × 20 mL). The salt was dried under vacuum to afford 2.55 g (31%) of the title compound (enantiomer B and (S)-(+)-mandelic acid, HPLC 97% ee) as a white solid. The mother liquor was evaporated to dryness before 0.5 M aqueous sodium hydroxide solution (20 mL) was added. The aqueous solution was extracted with dichloromethane (3 × 10 mL) and the combined organic phases were dried over MgSO ₄ and evaporated at rt under vacuum to a mixture of 7: 3 (Enantiomer A: Enantiomer B) of the enantiomer. The corresponding tan paste was obtained (3.24 g, 59%).

((R)-(-)-mandelic acid reacted with mother liquor to give enantiomer A, R _t = 24.3 min)

Methanol (35) in a 100 mL flask equipped with a magnetic stirrer containing a solution of a mixture of 7: 3 (enantiomer A: enantiomer B) (3.24 g, 11 mmol) of the enantiomer in methanol (30 mL) at 35 ° C (R)-(-)-mandelic acid (1.09 g, 7.2 mmol) dissolved in mL) was added. The resulting mixture was stirred at an internal temperature of 35 ° C. for 24 hours. The crystallized solid was filtered through a sintered glass funnel, washed with methanol at room temperature (3 × 16 mL) and dried under vacuum to afford 3.08 g (63%) of the title compound (enantiomers A and (R)-(- ) -Mandelic acid, HPLC 97% ee) was obtained as a white solid.

Step C

Formation of Dihydrochloride of Enantiomer A from the Corresponding Mandelate

To a 250 mL flask equipped with a magnetic stirrer containing enantiomer A (3.08 g, 6.9 mmol) of mandelate salt was added 1 M sodium hydroxide solution (30 mL) and dichloromethane (60 mL). After 5 minutes of vigorous stirring, the organic phase was recovered and the aqueous phase was extracted with dichloromethane (2 x 60 mL). The combined organic phases were washed with brine (30 mL), dried over MgS0 ₄ and evaporated to dryness at room temperature. The resulting tan paste was dissolved in 1 M aqueous hydrogen chloride solution (50 mL), and the solvent was evaporated to dryness to obtain a white solid. When the solid was dried under high vacuum at 25 ° C. until constant weight, it was melted and recrystallized to give the title compound as a yellow solid (1.97 g, 78%, HPLC 97.8% ee).

Formation of Dihydrochloride of Enantiomer B from the Corresponding Mandelate

To a 100 mL flask equipped with a magnetic stirrer containing enantiomer B (2.1 g, 4.7 mmol) of the mandelate salt was added 1 M sodium hydroxide solution (20 mL) and dichloromethane (40 mL). After 5 minutes of vigorous stirring, the organic phase was recovered and the aqueous phase was extracted with dichloromethane (2 x 40 mL). The combined organic phases were washed with brine (20 mL), dried over MgS0 ₄ and evaporated to dryness at room temperature. The resulting tan paste was dissolved in 1 M aqueous hydrogen chloride solution (30 mL), and the solvent was evaporated to dryness to obtain a white solid. When this solid was dried under high vacuum at 25 ° C. until constant weight, it was melted and recrystallized to give the title compound as a yellow solid (1.57 g, 91%, HPLC 97.7% ee).

Chiral HPLC Conditions:

Sample: 2 mg eq in n-heptane / (ethanol-0.2% DEA) (90:10). Base / mL

Column: Chiracel AD-H

Solvent: n-heptane / (ethanol-0.2% DEA) (90:10)

Injection volume: 5 μl

6 shows the racemic mixture (dihydrochloride salt) before crystallization.

R _t (initial elution enantiomer A): 24.3 min

R _t (term eluting enantiomer B): 26.1 min

FIG. 7 shows the initial eluting enantiomer A (dihydrochloride salt) after crystallization.

8 shows the late eluted enantiomer B (dihydrochloride salt) after crystallization.

Step D

Boc-Protection of Early Elution Enantiomer A

2-bromo-N ^{6 , 9} -dimethyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-6-amine di-hydrochloride (0.94 g 2.56 mmol; mirror image Isomer A) was dissolved in tetrahydrofuran (50 mL) and treated with triethylamine (1.95 mL, 13.9 mmol) and di-tert-butyl dicarbonate (1.8 g, 8.55 mmol). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified using a Biotage Isolera One purification system using ethyl acetate / n-heptane gradients (5/95 to 30/70) to afford the title compound (enantiomer A) as an off-white solid (0.969). g, 96%).

Boc-protection of terminally eluted enantiomer B

The late eluted enantiomer B was treated as described above (steps C and D) to obtain the corresponding Boc-protected tricyclic building blocks.

337.3 Conclusion

Enantiomerically pure building blocks were prepared by separation of the racemic mixture through crystallization of the diastereomeric salts. The purity of the individual enantiomeric building blocks was 97.8% ee for enantiomer A and 97.7% ee for enantiomer B.

Example 214: Preparation of Compounds 214a and 214b (enantiomer of Compound 26) using the title compound from Preparation Example 336 (diastereomer separation)

214.1 Purpose and design of the study

The aim of this study is to synthesize two enantiomers of Compound 26, Compounds 214a and 214b, using enantiomeric rich building blocks prepared through diastereomeric separation.

214.2 Synthesis Scheme of Enantiomer-Rich Compound 214b

Step A

Tert-butanol (2 mL) was added 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos, 0.036 g, 0.075 mmol) and palladium (II) acetate (0.0056 g, 0.025 mmol). The mixture was degassed by sonication for 1 minute while passing a stream of argon through the solution. This mixture was heated in a sand-bath at ˜100 ° C. for 1 minute to produce a catalyst. The title compound of Preparation Example 336, commercially available 3,4-difluoro aniline (0.041 g, 0.31 mmol) and potassium carbonate (Prepared from the terminal diastereomer (0.1 g, 0.25 mmol) in a light red catalyst solution then 0.086 g, 0.625 mmol) was added. This mixture was heated in a sand-bath at ˜110 ° C. for 3 hours. The mixture was diluted with ethyl acetate (100 mL) and water (10 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified twice using Biotage Isolera flash purification (MeOH / DCM: 0-1% then EtOAc / n-heptane: 10-30%) system to give the title compound as an off-white solid (0.087 g, 97% ).

FIG. 8 depicts Boc-protected precursors of compound 214b derived from the terminal diastereomers.

Step B

The title compound (0.08 g, 0.045 mmol) from Step A above was dissolved in dichloromethane (2.0 mL) and treated with a 2M solution of hydrogen chloride (2 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (5 mL) and dried under reduced pressure to give the title compound as an off white solid (0.068 g, 97%).

214.3 Synthesis Scheme of Enantiomer-Rich Compound 214a

For the enantiomer-rich building block derived from the initial diastereomer of Preparation Example 336, the same procedure as in Step A described for the synthesis of Compound 214b was applied to obtain a Boc-protected precursor of Compound 214a.

9 shows the Boc-protected precursor of 214a derived from the initial diastereomers.

For enantiomeric rich building blocks derived from the initial diastereomers, compound 214a was obtained by applying the same procedure as described for step B described for the synthesis of compound 214b.

214.4 Conclusion

Building blocks obtained from the separation of diastereomers were used to prepare enantiomer-rich compounds 214a and 214b. Building blocks derived from early diastereomers yielded enantiomeric compounds (Boc-protected compound 214a) containing 89% of the initial enantiomers and 10.6% of the terminal enantiomers. Building blocks derived from the terminal diastereomers yielded enantiomeric compounds (Boc-protected compound 214b) containing 28.5% of the initial enantiomer and 69.4% of the terminal enantiomer.

Example 215: Preparation of compounds 215a and 215b (enantiomer of Compound 26) using the title compound from Preparation Example 337 (separation by crystallization)

215.1 Purpose and design of the study

The goal of this study is to synthesize two enantiomers of Compound 26, Compounds 215a and 215b, using enantiomerically pure building blocks prepared through crystallization of the salts of diastereomers.

215.2 Synthesis Scheme of Enantiomerically Pure Compound 215b

Step A

Tert-butanol (13 mL) was added 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos, 0.119 g, 0.25 mmol) and palladium (II) acetate (0.0198 g, 0.084 mmol). The mixture was degassed by sonication for 1 minute while passing a stream of argon through the solution. This mixture was heated in a sand-bath at ˜100 ° C. for 1 minute to produce a catalyst. Subsequently, the title compound of Preparation Example 337 obtained from the initial eluting enantiomer A (0.33 g, 0.84 mmol) in a light red catalyst solution, a commercially available 3,4-difluoro aniline dissolved in 1 mL tert-butanol ( 0.125 g, 0.99 mmol) and potassium carbonate (0.257 g, 1.85 mmol) were added. This mixture was heated in a sand-bath at ˜110 ° C. for 3 hours. The mixture was diluted with ethyl acetate (250 mL) and water (25 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified using Biotage Isolera One purification system with ethyl acetate / n-heptane gradient (5/95 to 30/70) to give the title compound as an off white solid (0.35 g, 95%).

Step B

The title compound (0.35 g, 0.79 mmol) from step A was dissolved in dichloromethane (8 mL). The solution was cooled at 0 ° C. and then treated with a 2 M solution of hydrogen chloride (8 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (15 mL) and dried to give the title compound as an off white solid (0.32 g, 95%).

215.3 Synthesis Scheme of Enantiomerically Pure Compound 215a

Step A

Tert-butanol (4 mL) was added 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos, 0.031 g, 0.065 mmol) and palladium (II) acetate (0.0049 g, 0.022 mmol). The mixture was degassed by sonication for 1 minute while passing a stream of argon through the solution. This mixture was heated in a sand-bath at ˜100 ° C. for 1 minute to produce a catalyst. Subsequently, the title compound of Preparation Example 337 obtained from the late eluted enantiomer B (0.086 g, 0.218 mmol) in a light red catalyst solution, a commercially available 3,4-difluoro aniline dissolved in 1 mL of tert-butanol ( 0.024 ml, 0.240 mmol) and potassium carbonate (0.060 g, 0.436 mmol) were added. This mixture was heated in a sand-bath at ˜110 ° C. for 3 hours. The mixture was diluted with ethyl acetate (250 mL) and water (25 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified using Biotage Isolera One purification system with ethyl acetate / n-heptane gradient (10/90 to 30/70) to afford the title compound as an off-white solid (0.095 g, 98%).

Step B

The title compound (0.095 g, 0.21 mmol) from step A was dissolved in dichloromethane (4 mL). The solution was cooled at 0 ° C. and then treated with a 2 M solution of hydrogen chloride (2 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (10 mL) and dried to give the title compound as an off white solid (0.078 g, 87%).

215.4 Conclusion

Enantiomerically pure compounds 215a and 215b were prepared using enantiomeric building blocks obtained through crystallization of the salts of diastereomers.

Example 216 Preparation of Compounds 216a and 216b (enantiomer of Compound 42) using the title compound from Preparation Example 336 (diastereoisomeric separation)

216.1 Purpose and design of the study

The goal of this study is to synthesize two enantiomers of Compound 42, 216a and 216b, using enantiomeric rich building blocks prepared through diastereomeric separation.

216.2 Synthesis Scheme of Enantiomer-Rich Compound 216b

Step A

Tert-butanol (2 mL) was added 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos, 0.0108 g, 0.022 mmol) and palladium (II) acetate (0.0017 g, 0.0076 mmol). The mixture was degassed by sonication for 1 minute while passing a stream of argon through the solution. This mixture was heated in a sand-bath at ˜100 ° C. for 1 minute to produce a catalyst. The title compound of Preparation Example 336, commercially available 4-morpholinoaniline (0.0169 g, 0.095 mmol) and potassium carbonate (0.0262 g), then obtained from the terminal diastereomer (0.03 g, 0.076 mmol) in a light red catalyst solution , 0.19 mmol) was added. This mixture was heated in a sand-bath at ˜110 ° C. for 3 hours. The mixture was diluted with ethyl acetate (100 mL) and water (10 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and the solvent removed. The residue was purified twice using Biotage Isolera flash purification (MeOH / DCM: 0-1% then EtOAc / n-heptane: 10-30%) system to give the title compound as an off-white solid (0.024 g, 64% ).

Step B

The title compound (0.02 g, 0.040 mmol) from step A was dissolved in dichloromethane (2.0 mL) and treated with a 2 M solution of hydrogen chloride (0.5 mL) in diethylether. The mixture was stirred at rt overnight, and the precipitate was collected by filtration. The solid was washed with diethyl ether (5 mL) and dried under reduced pressure to afford the title compound as a white solid (0.016 g, 99%).

216.2 Synthesis Scheme of Enantiomer-Rich Compound 216a

For the enantiomer-rich building block derived from the initial diastereomer of Preparation Example 336, Compound 216a was obtained by applying the same procedures as in Steps A and B described for the synthesis of Compound 216b.

216.4 Conclusion

Building blocks obtained from the separation of diastereomers were used to prepare enantiomer-rich compounds 216a and 216b.

Example 217: Preparation of Compounds 217a and 217b (enantiomer of Compound 156) using the title compound from Preparation Example 336 (diastereoisomeric separation)

217.1 Purpose and design of the study

The goal of this study is to synthesize two enantiomers of Compound 156, Compounds 217a and 217b, using enantiomeric rich building blocks prepared through diastereomeric separation.

217.2 Synthesis Scheme of Enantiomer-Rich Compound 217b

Step A

To a mixture of XPhos (0.0108 mg, 0.023 mmol) and palladium (II) acetate (0.0017 g, 0.008 mmol) was added 4 mL of degassed tert-butanol (sonication under argon stream). The resulting solution was heated to 80 ° C. for 90 seconds (until a deep red color was observed). Activated catalyst was obtained from the terminal diastereomer of Preparation Example 336, title compound (0.030 g, 0.076 mmol), 2,3-dihydrobenzo [b] [1,4] dioxin-6-amine (0.0115 g, 0.076 mmol) and potassium carbonate (0.021 g, 0.152 mmol) were transferred to a second vial. The resulting mixture was heated to 110 ° C. for 3 hours. The reaction mixture was concentrated to dryness. Purify the residue by Biotage flash chromatography on EtOAc / n-heptane 15% to 30% system to afford the title compound as a beige foam (0.036 g, 100%).

Step B

To a solution of the title compound of step A (0.034 g, 0.073 mmol) above in 4 mL of dichloromethane was added 2 M solution of hydrogen chloride in 0.050 mL of methanol and diethyl ether (0.183 ml, 0.366 mmol). The resulting mixture was stirred at rt for 12 h. After completion, the mixture was concentrated to dryness and a few drops of MeOH were added to dissolve the residue. Finally EtOAc was added to precipitate the product. The slurry was filtered and dried under vacuum for 2 hours to give the title compound as a yellow solid (0.016 g, 50%).

217.3 Synthesis Scheme of Enantiomer-Rich Compound 217a

For the enantiomer-rich building block derived from the initial diastereomer of Preparation Example 336, the same procedure as in Step A described for the synthesis of Compound 217b was applied to obtain a Boc-protected precursor of Compound 217a.

Step B

For enantiomeric rich building blocks derived from the initial diastereomers, compound 217a was obtained (0.015 g, 42%) by applying the same procedure as described in step B for synthesis of compound 217b.

217.4 Conclusion

Building blocks obtained from the separation of diastereomers were used to prepare enantiomer-rich compounds 217a and 217b.

Example 218 Preparation of Compounds 218a and 218b (enantiomer of Compound 156) using the title compound from Preparation Example 337 (separation by crystallization)

218.1 Purpose and design of the study

The goal of this study is to synthesize two enantiomers of Compound 156, Compounds 218a and 218b, using enantiomerically pure building blocks prepared through crystallization of the salts of diastereomers.

218.2 Synthesis Scheme of Enantiomerically Pure Compound 218b

Step A

To a mixture of XPhos (0.0272 mg, 0.057 mmol) and palladium (II) acetate (0.0042 g, 0.019 mmol) was added 4 mL of degassed tert-butanol (sonication under argon stream). The resulting solution was heated to 80 ° C. for 90 seconds (until a deep red color was observed). The activated catalyst was prepared from the initial eluted enantiomer A of the title compound of Preparation Example 337 (0.075 g, 0.190 mmol), 2,3-dihydrobenzo [b] [1,4] dioxin-6-amine (0.0288 mg , 0.190 mmol) and potassium carbonate (0.0526 mg, 0.380 mmol) were transferred to a second vial. The resulting mixture was heated to 110 ° C. for 3 hours. The reaction mixture was concentrated to dryness. Purification of the residue by Biotage flash chromatography on EtOAc / n-heptane 15% to 35% system gave the title compound as a white solid (0.083 g, 94%).

Step B

To a solution of the title compound of step A (0.082 g, 0.177 mmol) in 4 mL of dichloromethane was added 2 M solution of hydrogen chloride in 0.050 mL of methanol and diethyl ether (0.183 ml, 0.366 mmol). The resulting mixture was stirred at rt for 12 h. After completion, the mixture was concentrated to dryness and a few drops of MeOH were added to dissolve the residue. Finally EtOAc was added to precipitate the product. The slurry was filtered and dried under vacuum for 2 hours to give the title compound as a yellowish solid (0.074 g, 96%).

218.3 Synthesis Scheme of Enantiomer-Rich Compound 218a

For the enantiomerically pure building block derived from the late eluted enantiomer B of Preparation Example 337, the same procedure as in step A described for the synthesis of compound 218b was applied to obtain a Boc-protected precursor of compound 218a. .

Step B

For enantiomerically pure building blocks derived from the late eluted enantiomer B, the same procedure as described in step B described for the synthesis of compound 218b was applied to give compound 218a as a light yellow solid (0.069 g, 85%) .

Example 219: amyl Detroit beta (Aβ) _{1 -42} peptide inhibition of aggregation (ThT assay)

ThT assays were used to test the ability of racemic compounds and their enantiomers to inhibit amyloid peptide aggregation. To determine the IC ₅₀ , the following dilutions of the compounds were used in the ThT assay described above:

330 μM, 82.50 μM, 20.63 μM, 5.16 μM, 1.29 μM, 0.32 μM and 0.08 μM

The items of the present invention are summarized below.

1. Compounds of the following formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorps thereof;

here,

A is selected from the group consisting of

L ₁ is directionally selected from the group consisting of:

B is selected from the group consisting of:

here,

R ¹ , R ² , R ³ and R ⁴ are hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , alkyl, -O-alkyl, -C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, Heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, Heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl may be optionally substituted or any groups R ¹ / R ² / R ³ When / R ⁴ are adjacent, they are optionally combined to form a carbon atom and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatoms (eg, N, O and / or S) -containing moieties. 5- to 8-membered rings containing Can be formed, the rings of 5- to 8-members and may be substituted by NR ²⁰ R ^21;

For each occurrence, R ^a is hydrogen, alkyl, haloalkyl, S (O) _t NR ³⁰ R ³¹ , S (O) _t R ³⁰ , C (O) OR ³⁰ , C (O) R ³⁰ , and C (O) NR ³⁰ R ³¹ is independently selected from the group consisting of;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted, or R ²⁰ and R ²¹ , in combination with the nitrogen to which they are attached, are selected from a carbon atom and optionally O, S, or N Form a ring of 3- to 8-members containing one or more additional heteroatoms or optionally one or more heteroatoms (eg, N, O and / or S) -containing moieties. And, the ring of said 3-to 8-members may optionally be substituted;

X and Y are each independently selected from the group consisting of CR ^b and N;

t is 1 or 2;

p is 0, 1 or 2,

Provided the following compounds:

Is excluded.

2. for item 1,

A is selected from the group consisting of:

이고; L ₁ is

ego;

B is selected from the group consisting of:

here,

R ¹ , R ² , R ³ , R ⁴ , R ^a , R ²⁰ , X and Y have the same meaning as in item 1,

V is absent or NR ²⁰ R ²¹ ,

z is 1 or 2;

3. The compound of item 1 or item 2, wherein A has formula (i).

4. The compound of any one of the above items, wherein L ₁ has the formula (a), preferably p is zero.

,

또는

)로부터 각각 독립적으로 선택된 것인, 화합물.
5. The compound of any of the preceding items, wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen, halogen (eg F), CN, CF ₃ , CONR ³⁰ R ³¹ , —O-alkyl, heterocycloalkyl ( for example

,

or

Each independently selected).

6. For item 1, the formula (vii) in A is

Wherein the compound is selected from.

7. A compound according to any one of the items, R ^a may be hydrogen or C _{1 -4} alkyl.

8. For item 1, A is the following formula (i)

Compound having a.

9. For item 1, A is the following formula (ii)

Compound having a.

10. For item 1, A is represented by the following formula (iii)

Compound having a.

11. For item 1, A is the following formula (iv)

Compound having a.

12. For item 1, A is represented by formula (v)

Compound having a.

13. For item 1, A is the following formula (vi)

Compound having a.

14. For item 1, A is the following formula (vii)

Compound having a.

15. For item 1, L ₁ is represented by the following formula (a)

Compound having a.

16. For item 1, B is represented by the following formula (ix)

Compound having a.

17. The item 1, wherein B is the following formula (x)

Compound having a.

18. Item 1, wherein B is the following formula (xi)

Compound having a.

19. For item 1, B is the following formula (xii)

Compound having a.

20. Item 1, wherein B is the following formula (xiii)

Compound having a.

21. A compound of item 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;

here,

이고, A is

ego,

이고, L ₁ is

ego,

B is

또는

이고,

or

ego,

here,

R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, hetero Each independently selected from the group consisting of aryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, hetero Aryl, arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;

R &lt; ³ &gt; is hydrogen or halogen;

R ^a is hydrogen or alkyl;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;

Each Y is independently CH or N;

t is 1 or 2;

z is 1 or 2;

The compound of item 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;

here,

이고, A is

ego,

이고, L ₁ is

ego,

이고, B is

ego,

here,

R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;

R &lt; ³ &gt; is hydrogen or halogen;

R ^a is hydrogen or alkyl;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;

Each Y is independently CH or N;

t is 1 or 2;

z is 1 or 2;

The compound of item 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;

here,

이고, A is

ego,

이고, L ₁ is

ego,

이고, B is

ego,

here,

R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;

R &lt; ³ &gt; is hydrogen or halogen;

R ^a is hydrogen or alkyl;

For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;

R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;

Each Y is independently CH or N;

t is 1 or 2;

The compound of item 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;

here,

A is

또는

이고,

or

ego,

이고, L ₁ is

ego,

B is

&Lt; / RTI &gt;

25. The compound of any of the above items selected from the group consisting of:

26. The compound of any of items 1 through 25, wherein the compound comprises a radionuclide, wherein the compound excluded from item 1 is excluded.

27. A radiopharmaceutical formulation comprising a compound according to any one of items 1 to 25 comprising a radionuclide, wherein the compound excluded from item 1 is excluded or not excluded.

28. A pharmaceutical composition comprising the compound of any one of items 1 to 25, wherein the compound excluded from item 1 is excluded.

29. The pharmaceutical composition of item 28, further comprising a pharmaceutically acceptable carrier or excipient.

30. Use of a compound according to any one of items 1 to 25 for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with amyloid and / or amyloid-like protein. Use of a compound excluded from 1 or not excluded.

31. Use according to item 30, wherein the disease is a neurological disorder.

32. The neurological disorder according to item 31, which is Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, amyloid hereditary cerebral hemorrhage (Dutch type), Guam Parkinson's dementia complex or mild cognitive disorder (MCI). Use.

33. The use of item 32, wherein the neurological disorder is Alzheimer's disease.

34. The condition of item 30, wherein the disease is advanced nuclear paralysis, multiple sclerosis, inclusion body myositis (IBM), Creutzfeldt-Jakob disease, Parkinson's disease, HIV-related dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM). , Adult-onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration (eg age-related macular degeneration (AMD)), optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy Use.

35. A method for treating or preventing a disease or condition associated with amyloid and / or amyloid-like protein, comprising administering to a subject in need thereof an effective amount of a compound according to any one of items 1 to 25. Wherein the compound excluded from item 1 is excluded or not excluded.

36. The method of item 35, wherein the disease is a neurological disorder.

37. The neurological disorder according to item 36, which is Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, amyloid hereditary cerebral hemorrhage (Dutch type), Guam Parkinson's dementia complex or mild cognitive disorder (MCI). How.

38. The method of item 37, wherein the neurological disorder is Alzheimer's disease.

39. The disease of item 35, wherein the disease is advanced nuclear paralysis, multiple sclerosis, inclusion body myositis (IBM), Creutzfeldt-Jakob disease, Parkinson's disease, HIV-related dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM). , Adult-onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration (eg age-related macular degeneration (AMD)), optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy How.

40. The compound according to any one of items 1 to 25, for use in treating or preventing a disease or condition associated with amyloid and / or amyloid-like protein, wherein the compound excluded from item 1 is excluded or not excluded Phosphorus compounds.

41. The compound of item 40, wherein the disease is a neurological disorder.

42. The neurological disorder according to item 41, which is Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, amyloid hereditary cerebral hemorrhage (Dutch type), Guam Parkinson's dementia complex or mild cognitive disorder (MCI). Compound.

43. The compound of item 42, wherein the neurological disorder is Alzheimer's disease.

44. The method of item 40, wherein the disease is advanced nuclear paralysis, multiple sclerosis, inclusion body myositis (IBM), Creutzfeldt-Jakob disease, Parkinson's disease, HIV-related dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM). , Adult-onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration (eg age-related macular degeneration (AMD)), optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy Compound.

45. A mixture comprising a compound described in any one of items 1 to 25 and optionally one or more additional biologically active compounds and / or pharmaceutically acceptable carriers and / or diluents and / or excipients, excluded from item 1 A mixture wherein the compound is excluded or not excluded.

46. The mixture of item 45, wherein the additional biologically active compound is a compound used for the treatment of amyloidosis.

47. The item of item 45 or item 46, wherein the additional biologically active compound is an antibody, vaccine, compound against oxidative stress, anti-cell death compound, metal chelator, DNA damage inhibitors such as pyrenzepine and metabolites, 3- Amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), α-secretase activator, β- and γ-secretase inhibitors, tau protein, neurotransmitters, β- Sheet breakers, attractants for amyloid clearing / depleting cell components, inhibitors of N-terminal truncated amyloid beta, including pyroglutamated amyloid beta 3-42, anti-inflammatory molecules, or Cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and / or galantamine, M1 agonists and other drugs including any amyloid or tau modified drugs and nutritional supplements The mixture is selected from the group consisting of.

48. The mixture of item 47 wherein the additional biologically active compound is a cholinesterase inhibitor (ChEI).

49. The method of item 47, wherein the additional biologically active compound consists of tacrine, rivastigmine, donepezil, galantamine, niacin, and memantine. Mixtures selected from the group.

50. The mixture of item 45, wherein the additional biologically active compound is any functionally equivalent antibody or an antibody comprising a functional part thereof, in particular a monoclonal antibody.

51. The mixture of item 50, wherein said any functionally equivalent antibody or antibody comprising a functional site thereof, in particular a monoclonal antibody, is an antibody that binds to amyloid β.

52. The item of item 50 or item 51, wherein the antibody, in particular monoclonal antibody, comprising any functionally equivalent antibody or functional site thereof, comprises amyloid monomeric and / or polymeric soluble amyloid peptides, in particular β-amyloid Monomeric peptides such as Aβ monomeric peptides 1-39; Polymeric soluble β-amyloid peptides comprising 1-40, 1-41, or 1-42, and / or a plurality of Aβ monomeric units, among others Aβ comprising a plurality of Aβ _1-42 monomeric units _In co-incubation with _1-42 monomeric and / or Aβ polymeric soluble amyloid peptides, the antibody inhibits aggregation of Aβ monomers into high molecular weight polymeric fibrils or filaments Amyloid monomeric peptides, in particular β-amyloid monomeric peptides such as Aβ monomeric peptides 1-39; In co-incubation with preformed high molecular weight polymeric amyloid fibrils or filaments, formed in particular by aggregation of 1-40, 1-41 or 1-42, in particular Aβ _1-42 monomeric peptides A mixture that is an antibody capable of dissolving the formed polymeric fibrils or filaments.

53. The mixture of item 50, wherein the antibody is a chimeric antibody or functional site or a humanized antibody or functional site.

54. The antibody of item 50, wherein the antibody is one of the following hybridoma cell lines:

a) FP 12H3 deposited as DSM ACC2752, dated December 01, 2005 and December 09, 2005, respectively;

b) FP 12H3-C2 deposited as DSM ACC2750 dated December 01, 2005 and December 09, 2005, respectively;

c) FP 12H3-G2 deposited as DSM ACC2751, dated December 01, 2005 and December 09, 2005, respectively;

d) ET 7E3, deposited December 08, 2005 with DSM ACC2755; And

e) EJ 7H3 deposited on December 08, 2005 with DSM ACC2756.

A mixture which is a monoclonal antibody selected from the group of antibodies having the characteristic properties of the antibody prepared by.

55. The cell line according to item 50, wherein the antibody is selected from the following hybridoma cell lines:

a) FP 12H3 deposited as DSM ACC2752, dated December 01, 2005 and December 09, 2005, respectively;

b) FP 12H3-C2 deposited as DSM ACC2750 dated December 01, 2005 and December 09, 2005, respectively;

c) FP 12H3-G2 deposited as DSM ACC2751, dated December 01, 2005 and December 09, 2005, respectively;

d) ET 7E3, deposited December 08, 2005 with DSM ACC2755; And

e) EJ 7H3 deposited on December 08, 2005 with DSM ACC2756.

A mixture that is a monoclonal antibody selected from the group of antibodies prepared by.

56. The mixture of item 50, wherein the antibody is a humanized antibody exhibiting the light and heavy chains set forth in SEQ ID NO: 2 and SEQ ID NO: 4 of International Application No. PCT / US2007 / 073504.

57. The mixture of item 50, wherein the antibody is a humanized antibody exhibiting the light chain variable regions and heavy chain variable regions set forth in SEQ ID NO: 1 and SEQ ID NO: 3 of International Application No. PCT / US2007 / 073504.

The item of item 45, wherein the additional biologically active compound comprises a single or repeated stretch of a plurality of consecutive amino acid residues from the N-terminal portion of the Aβ peptide, in particular Aβ consisting of a stretch of 13 to 15 consecutive amino acid residues. The mixture is an antigenic peptide fragment.

59. The mixture of item 58, wherein the Aβ antigenic peptide fragment is an Aβ _1-15 peptide antigen.

60. The antibody of item 58, wherein the Aβ _1-15 peptide antigen is modified by covalently linked palmitoyl residues, in particular 2-4, more particularly 4 residues, at each end of the peptide reconstituted in liposomes. Mixture is a palmitoylated Aβ _1-15 peptide antigen.

61. The mixture of any of items 45 through 60, wherein the compound and / or the additional biologically active compound is present in a therapeutically effective amount.

62. Steps below:

(a) contacting a sample or specific body part or body region suspected of containing amyloid protein with a compound described in any one of item 1 to item 25, wherein the compound excluded from item 1 is excluded or excluded Step;

(b) allowing the compound to bind to the amyloid protein;

(c) detecting a compound attached to the protein; And

(d) optionally correlating the presence or absence of a compound bound to the amyloid protein with the presence or absence of an amyloid protein in the sample or a specific body part or body region.

And collecting data for diagnosis of amyloid-related disease or condition in the sample or patient.

63. Steps below:

(a) providing a sample representative of the tissue and / or body fluid under investigation;

(b) testing said sample for the presence of amyloid protein with a compound as described in any of items 1 to 25, wherein the compound excluded from item 1 is excluded or not excluded;

(c) measuring the amount of the compound bound to the amyloid protein; And

(d) calculating a plaque burden in the tissue and / or body fluid

Method for measuring the degree of amyloidogenic plaque load in tissue and / or body fluid comprising a.

64. The method of item 63, wherein the measurement in step (c) is performed to correlate the presence or absence of the compound bound to the amyloid protein with the presence or absence of the amyloid protein. How to measure the degree.

65. Steps below:

(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound described in any one of item 1 to item 25, wherein the compound excluded from item 1 is excluded or excluded , Wherein the compound specifically binds to the amyloid protein;

(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;

(c) detecting the formation of said compound / protein complex;

(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And

(e) optionally comparing the amount of compound / protein complex to a normal control value

, Sample compounds except within or in situ comprising detecting the specific binding of a compound according to any one item of item 1 to item 25 of the amyloid protein in (in situ), and item 1 containing the excluding or A method of collecting data for determining predisposition to amyloid-related diseases or conditions in a patient, which is not excluded.

66. Steps below:

(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound described in any one of item 1 to item 25, wherein the compound excluded from item 1 is excluded or excluded , Wherein the compound specifically binds to the amyloid protein;

(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;

(c) detecting the formation of said compound / protein complex;

(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And

(e) optionally comparing the amount of compound / protein complex to a normal control value

A method of collecting data for monitoring minimal residual disease in a patient after treatment with an antibody or vaccine composition comprising a.

67. Steps below:

(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound described in any one of item 1 to item 25, wherein the compound excluded from item 1 is excluded or excluded , Wherein the compound specifically binds to the amyloid protein;

(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;

(c) detecting the formation of said compound / protein complex;

(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And

(e) optionally comparing the amount of compound / protein complex to a normal control value

A method of collecting data for predicting responsiveness of a patient treated with an antibody or vaccine composition comprising a.

68. A test kit for detecting and / or diagnosing an amyloid-related disease or condition, comprising the compound of any one of items 1 to 25, wherein the compound excluded from item 1 is excluded or not excluded , Test kit.

69. The method of item 68, wherein the compound / protein complex is formed by binding to an amyloid protein and a container containing one or more compounds of any of items 1 to 25 to detect the formation of the compound / protein complex, wherein A test kit comprising instructions for the use of said compound for the purpose of correlating the presence or absence of a compound / protein complex with the presence or absence of said amyloid protein, wherein the compound excluded from item 1 is excluded or excluded That is, the test kit.

70. For the manufacture of a medicament for the treatment or prevention of eye diseases or conditions associated with pathological abnormalities / changes in the tissues of the visual system, in particular associated with amyloid-beta-related pathological abnormalities / changes in the tissues of the visual system, The use of a compound according to any one of items 1 to 25, wherein the compound excluded from item 1 is excluded or not excluded.

71. The condition according to item 70, wherein the ocular disease or condition is neurodegradation, cortical visual defect, glaucoma, cataract due to beta-amyloid deposition, ocular amyloidosis, primary retinal degeneration, macular degeneration, eg age-related macular degeneration , Optic nerve drusen, optic neuropathy, optic neuritis, and lattice dystrophy.

72. Particularly in tissues of the visual system related to pathological abnormalities / changes in tissues of the visual system, comprising administering to a subject in need thereof an effective amount of a compound as described in any of items 1 to 25 A method of treating or preventing an ocular disease or condition associated with amyloid-beta-related pathological abnormalities / changes of the method, wherein the compound excluded from item 1 is excluded or not excluded.

73. The item of item 72, wherein the ocular disease or condition is neurodegradation, cortical visual defect, glaucoma, cataract due to beta-amyloid deposition, ocular amyloidosis, primary retinal degeneration, macular degeneration, eg age-related macular degeneration , Optic nerve drusen, optic neuropathy, optic neuritis, and lattice dystrophy.

74. The ocular disease or condition according to any of items 1 to 25, associated with pathological abnormalities / changes in the tissues of the visual system, in particular associated with amyloid-beta-related pathological abnormalities / changes in the tissues of the visual system. A compound for use in the treatment or prophylaxis of a compound, wherein the compound excluded from item 1 is excluded or not excluded.

75. The condition of item 74, wherein the ocular disease or condition is neurodegradation, cortical visual defect, glaucoma, cataracts due to beta-amyloid deposition, ocular amyloidosis, primary retinal degeneration, macular degeneration, eg age-related macular degeneration , Optic nerve drusen, optic neuropathy, optic neuritis, and lattice dystrophy.

76. A compound according to any one of items 1 to 25, for use in inhibiting protein aggregation, in particular for use in inhibiting Aβ _1-42 aggregation, tau aggregation or alpha-synuclein aggregation, excluded from item 1 Compound is excluded or not excluded.

77. For the manufacture of a medicament for (a) reducing the β-amyloid plaque load, and / or (b) inhibiting the formation of β-amyloid plaque and / or (c) delaying the increase in amyloid load in the brain of the patient. The use of a compound according to any one of items 1 to 25, wherein the compound excluded from item 1 is excluded or not excluded.

78. (a) reducing the β-amyloid plaque load, and / or (b) the β-amyloid, comprising administering an effective amount of the compound of any one of items 1 to 25 to a subject in need thereof. A method of inhibiting plaque formation, and / or (c) retarding an increase in amyloid load in the brain of a patient, wherein the compound excluded from item 1 is excluded or not excluded.

79. The method of any one of items 1 to 25, wherein (a) reduce the β-amyloid plaque load, and / or (b) inhibit the formation of β-amyloid plaques, and / or (c) amyloid in the brain of the subject A compound for use in delaying an increase in load, wherein the compound excluded from item 1 is excluded or not excluded.

80. The use of item 77, the method of item 78 or the compound of item 79, wherein reducing the β-amyloid plaque load, inhibiting the formation of β-amyloid plaque and / or retarding the increase in amyloid load is β in the brain. A use, method, or compound that results in a reduction and / or amelioration of the effect of a disease or condition caused by or associated with amyloid plaque formation.

81. A compound exempted from item 1 as a use of a compound according to any one of items 1 to 25 for the manufacture of a medicament for maintaining or increasing the cognitive memory capacity of a subject suffering from memory impairment. Is excluded or not excluded.

82. A method of maintaining or increasing the cognitive memory ability of a subject suffering from a memory disorder, comprising administering to a subject in need thereof an effective amount of a compound as described in any one of items 1 to 25. Wherein the compound excluded from is excluded or not excluded.

83. The compound of any of items 1 through 25, wherein the compound for use in maintaining or increasing the cognitive memory ability of the subject suffering from a memory disorder, wherein the compound excluded from item 1 is excluded or excluded.

84. The use of item 30, the method of item 35 or the compound of item 40, wherein the amyloid-related condition is characterized by a loss of cognitive memory capacity.

85. Use, method, or compound of item 84, wherein the treatment of the amyloid-related condition characterized by a loss of cognitive memory capacity results in an increase in retention of cognitive memory capacity.

86. Use, method, or compound of item 84, wherein the treatment of the amyloid-related condition characterized by a loss of cognitive memory capacity results in a complete restoration of cognitive memory capacity.

<110> AC Immune S.A.   <120> Novel compounds for the treatment of diseases associated with amyloid or amyloid-like proteins <130> S1590 PCT <150> EP 10 16 0223.3 <151> 2010-04-16 <150> EP 10 19 1616.1 <151> 2010-11-17 <160> 4 <170> PatentIn version 3.3 <210> 1 <211> 112 <212> PRT <213> Artificial sequence <220> <221> source <223> / note = "Description of artificial sequence: artificial humanized C2 HuVK 1 variable light chain" <400> 1 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser             20 25 30 Asn Gly Asp Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser         35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro     50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser                 85 90 95 Thr His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 2 <211> 219 <212> PRT <213> Artificial sequence <220> <221> source <223> / note = "Description of artificial sequence: artificial humanized C2 light chain" <400> 2 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser             20 25 30 Asn Gly Asp Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser         35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro     50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser                 85 90 95 Thr His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu         115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe     130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser                 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu             180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser         195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 <210> 3 <211> 112 <212> PRT <213> Artificial sequence <220> <221> source <223> / note = "Description of artificial sequence: artificial humanized C2 HuVH AF 4 variable heavy chain" <400> 15 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val         35 40 45 Ala Ser Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser             100 105 110 <210> 4 <211> 439 <212> PRT <213> Artificial sequence <220> <221> source <223> / note = "Description of artificial sequence: artificial humanized C2 heavy chain" <400> 4 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val         35 40 45 Ala Ser Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser             100 105 110 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg         115 120 125 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr     130 135 140 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 145 150 155 160 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser                 165 170 175 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr             180 185 190 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys         195 200 205 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro     210 215 220 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 225 230 235 240 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val                 245 250 255 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp             260 265 270 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe         275 280 285 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp     290 295 300 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 305 310 315 320 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg                 325 330 335 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys             340 345 350 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp         355 360 365 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys     370 375 380 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 385 390 395 400 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser                 405 410 415 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser             420 425 430 Leu Ser Leu Ser Leu Gly Lys         435  

Claims (86)

A compound of formula (I)

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorps thereof;
here,
A is selected from the group consisting of

L ₁ is directionally selected from the group consisting of:

B is selected from the group consisting of:

here,
R ¹ , R ² , R ³ and R ⁴ are hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , -N (R ³⁰ ) -C (O) -R ³¹ , alkyl, -O-alkyl,- Each in the group consisting of C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl Independently selected, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl may be optionally substituted Or, if any groups R ¹ / R ² / R ³ / R ⁴ are adjacent, they are optionally combined to form a carbon atom and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatoms (eg For example, 5- containing N, O and / or S) -containing moieties May form a ring of the 8-member ring of the 5- to 8-members and may be substituted by NR ²⁰ R ²¹ or -O- alkyl, wherein said alkyl or optionally substituted, or

Lt; / RTI &gt;
For each occurrence, R ^a is hydrogen, alkyl, haloalkyl, S (O) _t NR ³⁰ R ³¹ , S (O) _t R ³⁰ , C (O) OR ³⁰ , C (O) R ³⁰ , and C (O) NR ³⁰ R ³¹ is independently selected from the group consisting of;
For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted, or R ²⁰ and R ²¹ , in combination with the nitrogen to which they are attached, are selected from a carbon atom and optionally O, S, or N Form a ring of 3- to 8-members containing one or more additional heteroatoms or optionally one or more heteroatoms (eg, N, O and / or S) -containing moieties. And, the ring of said 3-to 8-members may optionally be substituted;
X and Y are each independently selected from the group consisting of CR ^b and N;
t is 1 or 2;
p is 0, 1 or 2,
Provided the following compounds:

Is excluded. The method according to claim 1,
A is selected from the group consisting of:

L ₁ is

ego;
B is selected from the group consisting of:

here,
R ¹ , R ² , R ³ , R ⁴ , R ^a , R ²⁰ , X and Y have the same meaning as in claim 1,
V is absent or NR ²⁰ R ²¹ ,
z is 1 or 2; The compound of claim 1 or 2, wherein A has formula (i). The compound of any one of the preceding clauses, wherein L ₁ has the formula (a), preferably p is zero. The compound of claim ¹ , wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen, halogen (eg F), CN, CF ₃ , CONR ³⁰ R ³¹ , —O-alkyl, heterocycloalkyl (eg

,

or

Each independently selected). The compound of claim 1 wherein in formula (vii)

Wherein the compound is selected from. A compound according to any one of the terms, R ^a may be hydrogen or C _{1 -4} alkyl. The method according to claim 1, A is the following formula (i)

Compound having a. The method according to claim 1, A is the following formula (ii)

Compound having a. The method according to claim 1, A is the following formula (iii)

Compound having a. The method according to claim 1, wherein A is the formula (iv)

Compound having a. The method according to claim 1, A is the following formula (v)

Compound having a. The method according to claim 1, A is the following formula (vi)

Compound having a. The compound of claim 1, wherein A is represented by Formula (vii)

Compound having a. The method according to claim 1, L ₁ is the formula (a)

Compound having a. The method according to claim 1, wherein B is the following formula (ix)

Compound having a. The method according to claim 1, wherein B is the following formula (x)

Compound having a. The method according to claim 1, wherein B is the following formula (xi)

Compound having a. The method according to claim 1, wherein B is the following formula (xii)

Compound having a. The method according to claim 1, wherein B is the following formula (xiii)

Compound having a. The compound of claim 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
here,
A is

ego,
L ₁ is

ego,
B is

or

ego,
here,
R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , -CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, hetero Each independently selected from the group consisting of aryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, hetero Aryl, arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;
R &lt; ³ &gt; is hydrogen or halogen;
R ^a is hydrogen or alkyl;
For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;
Each Y is independently CH or N;
t is 1 or 2;
z is 1 or 2; The compound of claim 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
here,
A is

ego,
L ₁ is

ego,
B is

ego,
here,
R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;
R &lt; ³ &gt; is hydrogen or halogen;
R ^a is hydrogen or alkyl;
For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;
Each Y is independently CH or N;
t is 1 or 2;
z is 1 or 2; The compound of claim 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
here,
A is

ego,
L ₁ is

ego,
B is

ego,
here,
R ¹ And R ² is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl are each independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl , Arylalkyl and heteroarylalkyl may be optionally substituted, or R ¹ And when R ² are adjacent, they are optionally combined to form a ring of 5- or 6-members containing a carbon atom and optionally one or two heteroatoms or heteroatom-containing moieties NR ⁵⁰ selected from O, S, or N; Can form;
R &lt; ³ &gt; is hydrogen or halogen;
R ^a is hydrogen or alkyl;
For each occurrence, R ^b is hydrogen, halogen, CN, CF ₃ , CONR ³⁰ R ³¹ , alkyl, —O-alkyl, —C (O) O-alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, Independently selected from the group consisting of fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoro Roalkyl, heterocycloalkylalkyl, alkenyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
For each occurrence, R ³⁰ , R ³¹ , R ²⁰ and R ²¹ are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, Each independently selected from the group consisting of heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl , Aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl may be optionally substituted;
R ⁵⁰ is for each occurrence R ²⁰ , S (O) _t NR ²⁰ R ²¹ , S (O) _t R ²⁰ , C (O) OR ²⁰ , C (O) R ²⁰ C (= NR ^a ) NR ²⁰ R ²¹ , C (═NR ²⁰ ) NR ²¹ R ^a , C (═NOR ²⁰ ) R ²¹ or C (O) NR ²⁰ R ²¹ ;
Each Y is independently CH or N;
t is 1 or 2; The compound of claim 1 having the formula (I):

And all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
here,
A is

or

ego,
L ₁ is

ego,
B is

&Lt; / RTI &gt; The compound of any one of the preceding clauses selected from the group consisting of:

The compound of any one of claims 1-25, wherein the compound comprises a radionuclide, wherein the compound excluded from claim 1 is excluded. A radiopharmaceutical formulation comprising a compound according to any one of claims 1 to 25 comprising a radionuclide, wherein the compound excluded from claim 1 is excluded or excluded. A pharmaceutical composition comprising the compound of any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded. The pharmaceutical composition of claim 28, further comprising a pharmaceutically acceptable carrier or excipient. The use of a compound according to any one of claims 1 to 25 for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with amyloid and / or amyloid-like protein, as claimed in claim 1 The excluded compound is excluded or not excluded. 31. The use of claim 30, wherein the disease is a neurological disorder. The neurological disorder of claim 31, wherein the neurological disorder is Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, amyloid hereditary cerebral hemorrhage (Dutch type), Guam Parkinson's dementia complication or mild cognitive disorder (MCI). Usage. The use of claim 32, wherein the neurological disorder is Alzheimer's disease. 31. The disease of claim 30, wherein the disease is advanced nuclear paralysis, multiple sclerosis, inclusion body myositis (IBM), Creutzfeldt-Jakob disease, Parkinson's disease, HIV-related dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), adult Onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration (eg age-related macular degeneration (AMD)), optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy Usage. A method for treating or preventing a disease or condition associated with amyloid and / or amyloid-like protein, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 25 , The compound excluded from claim 1 is excluded or not excluded. 36. The method of claim 35, wherein the disease is a neurological disorder. The neurological disorder of claim 36, wherein the neurological disorder is Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, amyloid hereditary cerebral hemorrhage (Dutch type), Guam Parkinson's dementia complication or mild cognitive disorder (MCI). Way. The method of claim 37, wherein the neurological disorder is Alzheimer's disease. 36. The disease of claim 35, wherein the disease is advanced nuclear paralysis, multiple sclerosis, inclusion body myositis (IBM), Creutzfeldt-Jakob disease, Parkinson's disease, HIV-related dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), adult Onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration (eg age-related macular degeneration (AMD)), optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy Way. The compound of any one of claims 1-25, wherein the compound for use in treating or preventing a disease or condition associated with amyloid and / or amyloid-like protein, wherein the compound excluded from claim 1 is excluded or not excluded. compound. The compound of claim 40, wherein the disease is neuropathic. The method of claim 41, wherein the neurological disorder is Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, amyloid hereditary cerebral hemorrhage (Dutch type), Guam Parkinson's dementia complication or mild cognitive disorder (MCI). compound. The compound of claim 42, wherein the neurological disorder is Alzheimer's disease. 41. The disease of claim 40, wherein the disease is advanced nuclear paralysis, multiple sclerosis, inclusion body myositis (IBM), Creutzfeldt-Jakob disease, Parkinson's disease, HIV-related dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), adult Onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration (eg age-related macular degeneration (AMD)), optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy compound. A compound comprising a compound according to any one of claims 1 to 25 and optionally at least one additional biologically active compound and / or a pharmaceutically acceptable carrier and / or diluent and / or excipient, wherein the compound excluded from claim 1 is Mixtures that are excluded or not excluded. The mixture of claim 45, wherein the additional biologically active compound is a compound used for the treatment of amyloidosis. The method of claim 45 or 46, wherein the additional biologically active compound is an antibody, vaccine, compound against oxidative stress, anti-cell death compound, metal chelator, DNA damage inhibitors such as pyrenzepine and metabolites, 3-amino-. 1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), α-secretase activator, β- and γ-secretase inhibitors, tau protein, neurotransmitters, β-sheet breakers , An attractant to amyloid clearing / depleting cell components, inhibitors of N-terminal truncated amyloid beta, including pyroglutamated amyloid beta 3-42, anti-inflammatory molecules, or cholinesterases Inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and / or other drugs, including galantamine, M1 agonists and any amyloid or tau modified drugs and nutritional supplements Mixtures selected from the group consisting of: 48. The mixture of claim 47, wherein said additional biologically active compound is a cholinesterase inhibitor (ChEI). 48. The method of claim 47, wherein the additional biologically active compound is in the group consisting of tacrine, rivastigmine, donepezil, galantamine, niacin and memantine. The mixture selected. The mixture of claim 45, wherein the additional biologically active compound is any functionally equivalent antibody or antibody comprising a functional part thereof, in particular a monoclonal antibody. 51. The mixture of claim 50, wherein said any functionally equivalent antibody or antibody comprising a functional site thereof, in particular a monoclonal antibody, is an antibody that binds amyloid β. The antibody of claim 50 or 51, wherein the antibody, in particular monoclonal antibody, comprising any functionally equivalent antibody or functional site thereof, comprises amyloid monomeric and / or polymeric soluble amyloid peptides, in particular β-amyloid monomeric. Peptides such as Aβ monomeric peptides 1-39; Polymeric soluble β-amyloid peptides comprising 1-40, 1-41, or 1-42, and / or a plurality of Aβ monomeric units, among others Aβ comprising a plurality of Aβ _1-42 monomeric units _In co-incubation with _1-42 monomeric and / or Aβ polymeric soluble amyloid peptides, the antibody inhibits aggregation of Aβ monomers into high molecular weight polymeric fibrils or filaments Amyloid monomeric peptides, in particular β-amyloid monomeric peptides such as Aβ monomeric peptides 1-39; In co-incubation with preformed high molecular weight polymeric amyloid fibrils or filaments, formed in particular by aggregation of 1-40, 1-41 or 1-42, in particular Aβ _1-42 monomeric peptides A mixture that is an antibody capable of dissolving the formed polymeric fibrils or filaments. The mixture of claim 50, wherein the antibody is a chimeric antibody or functional site thereof or a humanized antibody or functional site thereof. The method of claim 50, wherein the antibody comprises the following hybridoma cell lines:
a) FP 12H3 deposited as DSM ACC2752, dated December 01, 2005 and December 09, 2005, respectively;
b) FP 12H3-C2 deposited as DSM ACC2750 dated December 01, 2005 and December 09, 2005, respectively;
c) FP 12H3-G2 deposited as DSM ACC2751, dated December 01, 2005 and December 09, 2005, respectively;
d) ET 7E3, deposited December 08, 2005 with DSM ACC2755; And
e) EJ 7H3 deposited on December 08, 2005 with DSM ACC2756.
A mixture which is a monoclonal antibody selected from the group of antibodies having the characteristic properties of the antibody prepared by. The method of claim 50, wherein the antibody comprises the following hybridoma cell lines:
a) FP 12H3 deposited as DSM ACC2752, dated December 01, 2005 and December 09, 2005, respectively;
b) FP 12H3-C2 deposited as DSM ACC2750 dated December 01, 2005 and December 09, 2005, respectively;
c) FP 12H3-G2 deposited as DSM ACC2751, dated December 01, 2005 and December 09, 2005, respectively;
d) ET 7E3, deposited December 08, 2005 with DSM ACC2755; And
e) EJ 7H3 deposited on December 08, 2005 with DSM ACC2756.
A mixture that is a monoclonal antibody selected from the group of antibodies prepared by. The mixture of claim 50, wherein the antibody is a humanized antibody exhibiting the light and heavy chains set forth in SEQ ID NO: 2 and SEQ ID NO: 4 of International Application No. PCT / US2007 / 073504. The mixture of claim 50, wherein the antibody is a humanized antibody exhibiting the light chain variable region and heavy chain variable region set forth in SEQ ID NO: 1 and SEQ ID NO: 3 of International Application No. PCT / US2007 / 073504. The method of claim 45, wherein the additional biologically active compound comprises Aβ consisting of a single or repeated stretch of a plurality of consecutive amino acid residues from the N-terminal portion of the Aβ peptide, in particular a stretch of 13-15 consecutive amino acid residues. The mixture is an antigenic peptide fragment. The mixture of claim 58, wherein the Aβ antigenic peptide fragment is Aβ _1-15 peptide antigen. The palmitate of claim 58, wherein the Aβ _1-15 peptide antigen is, at each end of the peptide reconstituted in liposomes, palmi modified by covalently linked palmitoyl residues, in particular 2-4, more particularly 4 residues. A mixture, which is a palmitoylated Aβ _1-15 peptide antigen. 61. The mixture of any one of claims 45 to 60, wherein the compound and / or the additional biologically active compound is present in a therapeutically effective amount. The following steps:
(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound according to any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or excluded Step;
(b) allowing the compound to bind to the amyloid protein;
(c) detecting the compound attached to the protein; And
(d) optionally correlating the presence or absence of a compound bound to the amyloid protein with the presence or absence of an amyloid protein in the sample or a specific body part or body region.
And collecting data for diagnosis of amyloid-related disease or condition in the sample or patient. The following steps:
(a) providing a sample representative of the tissue and / or body fluid under investigation;
(b) testing said sample for the presence of amyloid protein with the compound of any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or not excluded;
(c) measuring the amount of the compound bound to the amyloid protein; And
(d) calculating a plaque burden in the tissue and / or body fluid
Method for measuring the degree of amyloidogenic plaque load in tissue and / or body fluid comprising a. The degree of amyloidogenic plaque load of claim 63, wherein the measuring in step (c) is performed to correlate the presence or absence of the compound bound to the amyloid protein with the presence or absence of the amyloid protein. How to measure. The following steps:
(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound according to any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or excluded , Wherein the compound specifically binds to the amyloid protein;
(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;
(c) detecting the formation of said compound / protein complex;
(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And
(e) optionally comparing the amount of compound / protein complex to a normal control value
That, the sample in or in situ comprising detecting the specific binding of a compound according to any one of claims 1 to 25 for the amyloid protein in (in situ), and the compounds excluded in claim 1 is excluded or included for A method of collecting data for determining predisposition to amyloid-related diseases or conditions in a patient, which is not excluded. The following steps:
(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound according to any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or excluded , Wherein the compound specifically binds to the amyloid protein;
(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;
(c) detecting the formation of said compound / protein complex;
(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And
(e) optionally comparing the amount of compound / protein complex to a normal control value
A method of collecting data for monitoring minimal residual disease in a patient after treatment with an antibody or vaccine composition comprising a. The following steps:
(a) contacting a sample or specific body part or body region suspected of containing an amyloid protein with a compound according to any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or excluded , Wherein the compound specifically binds to the amyloid protein;
(b) allowing the compound to bind to the amyloid protein to form a compound / protein complex;
(c) detecting the formation of said compound / protein complex;
(d) optionally correlating the presence or absence of said compound / protein complex with the presence or absence of amyloid protein in said sample or specific body part or body region; And
(e) optionally comparing the amount of compound / protein complex to a normal control value
A method of collecting data for predicting responsiveness of a patient treated with an antibody or vaccine composition comprising a. A test kit for the detection and / or diagnosis of an amyloid-related disease or condition, comprising the compound of any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or excluded Kit. The compound of claim 68, wherein the compound / protein complex is formed by binding to an amyloid protein and a container containing one or more compounds of claim 1 to detect the formation of the compound / protein complex, wherein the compound / A test kit comprising instructions for the use of said compound for the purpose of correlating the presence or absence of a protein complex with the presence or absence of said amyloid protein, wherein the compound excluded from claim 1 is excluded or excluded Phosphorus, test kit. Claim 1 for the preparation of a medicament for the treatment or prevention of eye diseases or conditions associated with pathological abnormalities / changes in tissues of the visual system, in particular associated with amyloid-beta-related pathological abnormalities / changes in tissues of the visual system, Use of a compound according to any one of claims 25 to 25, wherein the compound excluded from claim 1 is excluded or not excluded. The method of claim 70, wherein the ocular disease or condition is neurodegradation, cortical visual defect, glaucoma, cataract due to beta-amyloid deposition, ocular amyloidosis, primary retinal degeneration, macular degeneration, eg age-related macular degeneration, optic nerve Use selected from the group consisting of drusen, optic neuropathy, optic neuritis, and lattice dystrophy. An amyloid, particularly in tissues of the visual system, associated with pathological abnormalities / changes in the tissues of the visual system, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 25. A method of treating or preventing an ocular disease or condition associated with a beta-related pathological abnormality / change, wherein the compound excluded from claim 1 is excluded or excluded. The method of claim 72, wherein the ocular disease or condition is neurodegradation, cortical visual defect, glaucoma, cataract due to beta-amyloid deposition, ocular amyloidosis, primary retinal degeneration, macular degeneration, eg age-related macular degeneration, optic nerve The method is selected from the group consisting of drusen, optic neuropathy, optic neuritis, and lattice dystrophy. 26. The method according to any one of claims 1 to 25, wherein the ocular disease or condition is associated with pathological abnormalities / changes in tissues of the visual system, in particular associated with amyloid-beta-related pathological abnormalities / changes in tissues of the visual system. A compound for use in the treatment or prophylaxis, wherein the compound excluded from claim 1 is excluded or excluded. The method of claim 74, wherein the ocular disease or condition comprises neurolysis, cortical visual defect, glaucoma, cataracts due to beta-amyloid deposition, ocular amyloidosis, primary retinal degeneration, macular degeneration, eg age-related macular degeneration, optic nerve A compound selected from the group consisting of drusen, optic neuropathy, optic neuritis, and lattice dystrophy. The compound according to claim 1, which is excluded from claim 1 as a compound for use in inhibiting protein aggregation, in particular for use in inhibiting Aβ _1-42 aggregation, tau aggregation or alpha-synuclein aggregation. Compound is excluded or not excluded. Claims for the manufacture of a medicament for (a) reducing the β-amyloid plaque load and / or (b) inhibiting the formation of β-amyloid plaque and / or (c) delaying the increase in amyloid load in the brain of a patient. Use of a compound according to any one of claims 1 to 25, wherein the compound excluded from claim 1 is excluded or not excluded. (A) reducing the β-amyloid plaque load, and / or (b) reducing the β-amyloid plaque, the method comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 25. Inhibiting formation, and / or (c) retarding an increase in amyloid load in the brain of a patient, wherein the compound excluded from claim 1 is excluded or excluded. 26. The amyloid load of any one of claims 1 to 25, wherein (a) reducing the β-amyloid plaque load, and / or (b) inhibiting the formation of the β-amyloid plaque, and / or (c) the amyloid rod in the brain of the subject. A compound for use in delaying the increase of a compound, wherein the compound excluded from claim 1 is excluded or excluded. The use of claim 77, the method of claim 78, or the compound of 79, wherein reducing the β-amyloid plaque load, inhibiting the formation of β-amyloid plaque and / or retarding the increase of amyloid load is, in the brain, a β-amyloid Use, method, or compound that results in a reduction and / or amelioration of the effect of a disease or condition caused by or associated with the formation and deposition of plaques. Use of a compound according to any one of claims 1 to 25 for the manufacture of a medicament for maintaining or increasing the cognitive memory ability of a subject suffering from memory impairment, excluding compounds excluded from claim 1 Use or not excluded. A method of maintaining or increasing the cognitive memory ability of a subject suffering from a memory disorder, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 25, excluding from claim 1. Compound is excluded or not excluded. The compound of any one of claims 1-25, wherein the compound for use in maintaining or increasing the cognitive memory capacity of a subject suffering from a memory disorder, wherein the compound excluded from claim 1 is excluded or excluded. The use, method, or compound of claim 30, the method of claim 35, or the compound of claim 40, wherein the amyloid-related condition is characterized by a loss of cognitive memory ability. The use, method, or compound of claim 84 wherein the treatment of the amyloid-related condition characterized by a loss of cognitive memory capacity results in an increase in retention of cognitive memory capacity. The use, method, or compound of claim 84 wherein the treatment of the amyloid-related condition characterized by a loss of cognitive memory capacity results in a complete restoration of cognitive memory capacity.

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